RS54480B1 - IMIDAZOPYRIDASINE AS ACT KINASE INHIBITORS - Google Patents

Abstract

A compound of formula (I) wherein R1 is hydrogen. hydroxy. NR5R6, halogen, cyano, CO (NR8R9), C (O) OR8, C (O) (1-6C-alkyl), NHC (O) (1-6C-alkyl), NHS (O) 2R11, NHC (O ) NHR11, -S (O) n-1-6C-alkyl, -S (O) 2NR5R6 or a group selected from 1-6C-alkyl. 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, - (1-6C-alkyl) -aryl, - (1-6C-alkyl) -heteroaryl, -O- (3-7C-cycloalkyl), - O-aryl, -O- (3-7C-heterocyclyl), -O-heteroaryl. -O- (1-6C-alkyl) -heteroaryl, -O- (1-6C-alkyl) - (3-7C-heterocyclyl), -O- (1-6C-alkyl) -aryl, 2-6C-alkenyl , 2-6C-alkynyl. Wherein said group is optionally substituted, one or more times, same or different, with a substituent selected from the group consisting of: hydroxy. halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano. -C (O) NR8R9, -C (O) OR10, -NHC (O) R11, -NHC (O) NHR11, -NHS (O) 2R11, 3-7C-cycloalkyl, 3-7C-heterocyclyl. aryl.R2 is hydrogen. hydroxy, NR5R6. halogen. cyano. CO (NR8R9). C (O) OR8, C (O) (1-6C-alkyl), NHC (O) (1-6C-alkyl), NHS (O) 2R11, NHC (O) NHR11, -S (O) n-1 -6C-alkyl, -S (O) 2NR5R6 or a group selected from the group consisting of 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, - (1-6C-alkyl) -aryl , - (1-6C-alkyl) -heteroaryl, -O- (3-7C-cycloalkyl). -O-aryl, -O- (3-7C-heterocyclyl), -O-heteroaryl. -O- (1-6C-alkyl) -heteroaryl, -O- (1-6C-alkyl) - (3-7C-heterocyclyl), -O- (1-6C-alkyl) -aryl, 2-6C-alkenyl . 2-6C-alkynyl. Wherein said group is optionally substituted, one or more times, same or different, with a substituent selected from the group consisting of: hydroxy. halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano. -C (O) NR 8 R 9. -C (O) OR 10. -NHC (O) R11, -NHC (O) NHR11, -NHS (O) 2R11, 3-7C-heterocyclyl, aryl.R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO (NR8R9), C (O) OR8, C (O) (1-6C-alkyl), NHS (O) 2R11, NHC (O) NHR11, -S (O) n-1-6C-alkyl, -S (O) 2NR5R6 or a group selected from the group containing 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, - (1-6C-alkyl) -aryl, - (1-6C-alkyl) -heteroaryl, -O- ( 3-7C-cycloalkyl), -O-aryl, -O- (3-7C-heterocyclyl), -O-heteroaryl, -O- (1-6C-alkyl) -heteroaryl, -O- (1-6C-alkyl) ) - (3-7C-heterocyclyl), -O- (1-6C-alkyl) -aryl, NHC (O) (1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl, wherein said group optionally substituted, one or more times, same or different, with a substituent selected from the group consisting of: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano. -C (O) NR8R9, -C (O) OR10, -NHC (O) R11, -NHC (O) NHR11, -NHS (O) 2R11, 3-7C-heterocyclyl, aryl, R4 is optionally phenyl substituted one, two or three times, same or different, by a halogen atom; R5 is hydrogen, 1-6C-alk or, R6 is hydrogen, 1-6C-alkyl, R8 is hydrogen, 1-6C-alkyl optionally substituted by hydroxy, R9 is hydrogen, 1-6C-alkyl, R10 is hydrogen, 1-6C-alkyl, R11 is hydrogen, 1-6C-alkyl, X, Y is CH2; n is 0, 1, 2; or N-oxide, salt, tautomer or stereoisomer of said compound, or salt of said N-oxide, tautomer or stereoisomer. 13 patent claims.

Description

Field of application of this invention

This invention relates to substituted imidazopyridazines, to a process for their production and to their use.

Known technical background

Cancer is the second leading cause of death in the United States, killing 450,000 people annually. While significant progress has been made in identifying some of the likely environmental and genetic causes of cancer, there is still a need for additional therapeutic modalities that target cancer and related diseases. In particular, there is a need for therapeutic procedures for the treatment of diseases associated with growth/proliferation.

Cancer is a complex disease, which occurs after the selection process of cells with acquired functional abilities such as increased survival/resistance to apoptosis and unlimited proliferative potential. Thus, it is preferred to develop drugs for cancer therapy that target specific characteristics of established tumors.

One pathway that has been shown to mediate important survival signals in mammalian cells involves receptor tyrosine kinases such as platelet-derived growth factor (PDGF-R), human epidermal growth factor receptor 2/3 (HER2/3), or insulin-like growth factor 1 receptor (IGF-1 R). After activation with the help of ligands, the mentioned receptors activate the phosphatidylinositol 3-kinase (Pi3K)/Akt pathway. The phosphatidylinositol 3-kinase (Pi3K)/Akt protein kinase pathway is crucial for the control of cell growth, proliferation and survival during tumor progression. Therefore, in the class of serine-threonine specific signaling kinases, Akt (protein kinase B; PKB) with isoenzymes Akti (PKBcc), Akt2 (PKB p) and Akt3 (PKB v) is of great interest for therapeutic intervention. Akt is mainly activated in a Pi3-kinase-dependent manner, and the activation itself is regulated by the tumor suppressor PTEN (phosphatase and tensin homologue), which mainly acts as a functional antagonist of Pi3K.

The Pi3K/Akt pathway regulates fundamental cellular functions (eg, transcription, translation, growth, and survival), and is important in human diseases including diabetes and cancer. This pathway is often overactive in a wide range of tumor entities such as breast and prostate cancer. Upregulation can occur due to overexpression or constitutive action of receptor tyrosine kinases (for example, EGFR, HER2/3), which occurs upstream and is directly involved in activation, but there are also mutants that lead to loss of function in some components such as loss of PTEN. This pathway is a mat of genetic changes including mutation, amplification, and rearrangement that occur more frequently than any other pathway in any human tumor, with the possible exception of the p53 pathway and retinoblastoma. Alterations in the Pi3K/Akt pathway trigger a cascade of biological events that drive tumor progression, survival, angiogenesis, and metastasis.

Activation of Akt kinases allows increased nutrient uptake, causing the cell to switch to a glucose-dependent metabolism that redirects lipid precursors and amino acids into anabolic processes that support cell growth and proliferation. This metabolic phenotype with overactivated Akt leads to malignant processes, causing metabolic conversion towards aerobic glycolysis (Warburg effect). In this regard, the Pi3K/Akt pathway is considered to be crucial for survival despite adverse growth conditions such as glucose deprivation or hypoxia.

An additional aspect of the activated PI3K/Akt pathway is that it protects cells from programmed cell death ("apoptosis") and is thought to transmit a survival signal. Acting as a modulator of anti-apoptotic signals in tumor cells, the Pi3K/Akt pathway, especially Akt is a target for tumor therapy. Activated Akt phosphorylates and regulates several targets, for example BAD, GSK3 or FKHRL1, thereby acting on various signaling pathways such as cell survival, protein synthesis or cell movement. The Pi3K/Akt pathway also plays a major role in the resistance of tumor cells to conventional anti-tumor therapies. Blockade of the Pi3K/Akt pathway can therefore simultaneously inhibit tumor cell proliferation (for example, by inhibiting a metabolic effect) and sensitize to pro-apoptotic agents.

Akt inhibition selectively sensitizes tumor cells to apoptotic stimuli such as Trail, Camptothecin and Doxorubicin. Depending on the genetic background/molecular spectra of the tumor, Akt inhibitors can induce apoptotic cell death also in monotherapies.

Thus, Akt appears to be a suitable target for tumor treatment.

There are numerous publications that disclose compounds that inhibit Akt such as for example documents WO 2009/148887, WO 2009/148916, WO2010104933, WO20101 14780, WO201 1033265.

In a recent disclosure, Y. Li et al (Bioorg. Med. Chem. Lett. 2009, 19, 834-836 and references cited therein), difficulties in efforts to discover optimal Akt inhibitors are shown. The potential use of Akt inhibitors in multiple types of diseases, such as for example cancer, makes the discovery of new Akt inhibitors, in addition to those already present, a highly desirable goal.

Description of the invention

The solution to the aforementioned problem is to provide alternative Akt inhibitors. The novel imidazopyridazine compounds, which are described in detail in the following text, have already been found to act as Akt inhibitors suitable for the treatment of cancer.

According to a first aspect, the present invention relates to compounds of formula (I)

in which

R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHC(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, - S(0)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-Alkoxy, 3-7C-Cycloalkyl, Aryl, Heteroaryl, -(1-6C-Alkyl)-Aryl, -(1-6C-Alkyl)-Heteroaryl, -O-(3-7C

-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-7-cycloalkyl, 3-7C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHC(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, - S(0)2NR5R6 or a group which is selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O-heteroaryl, -O-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogeno, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-7C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, -S(0)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -0-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), - O-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl, NHC(0)(1-6C-alkyl), 2-6C-alkenyl. 2-6C-alkynyl, whereby the said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-7C-heterocyclyl, aryl,

R 4 is phenyl which is sometimes substituted one, two or three times, identically or differently, with a halogen atom;

R5 is hydrogen, 1-6C-alkyl,

R6 is hydrogen, 1-6C-alkyl,

R8 is hydrogen, 1-6C-alkyl which is sometimes substituted with hydroxy,

R9 is hydrogen, 1-6C-alkyl,

R10 is hydrogen, 1-6C-alkyl,

R11 is hydrogen, 1-6C-alkyl,

X, Y is CH2;

n is 0, 1, 2;

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

According to another aspect, the present invention relates to compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHC(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, - S(0)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-Alkoxy, 3-7C-Cycloalkyl, Aryl, Heteroaryl, -(1-6C-Alkyl)-Aryl, -(1-6C-Alkyl)-Heteroaryl, -O-(3-7C-Cycloalkyl), -O-Aryl, -0-(3-7C-Heterocyclyl), -O-Heteroaryl, -0-(1-6C-Alkyl)-Heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,

wherein said group is sometimes substituted, once or more, identically or differently, with a substituent selected from:

hydroxy, halogeno, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, - NHS(0)2R11, 3-7C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, C0(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHC(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, - S(0)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-Alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -0-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O -heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -O-(1-6C-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-Alkoxy, -NR8R9, cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, - NHS(0)2R11, 3-7C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHC(0)(1-6C-alkyl). NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, - S(0)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent which is selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, - NHS(0)2R11, 3-7C-heterocyclyl, aryl,

R 4 is phenyl which is sometimes substituted one, two or three times, identically or differently,

with a halogen atom;

R5 is hydrogen, 1-6C-alkyl,

R6 is hydrogen, 1-6C-alkyl,

R8 is hydrogen, 1-6C-alkyl,

R9 is hydrogen, 1-6C-alkyl,

R10 is hydrogen, 1-6C-alkyl,

R11 is hydrogen, 1-6C-alkyl,

X, Y is CH2;

n is 0,1,2;

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the present invention relates to compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHC(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-3C-alkyl, - S(0)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-Alkoxy, 3-6C-cycloalkyl, Aryl, Heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -0-(3-6C-cycloalkyl), -O-aryl, -0-(3-6C-heterocyclyl), -O-heteroaryl, -0-(1-3C-alkyl)-heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-Alkoxy, -NR8R9, Cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-6-Cycloalkyl, 3-6C-Heterocyclyl, Aryl,

R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHC(0)(1-3C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-3C-alkyl, - S(0)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-Alkoxy, 3-6C-cycloalkyl, Aryl, Heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -0-(3-6C-cycloalkyl), -O-aryl, -0-(3-6C-heterocyclyl), -O-heteroaryl, -0-(1-3C-alkyl)-heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl,

wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-6C-heterocyclyl,

aril,

R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-3C-alkyl, -S(0)2NR5R6, or a group selected from 1-3C-alkyl, 1-3C-alkoxy. 3-6C-cycloalkyl, aryl, heteroaryl, -

(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -0-(3-6C-cycloalkyl), -O-aryl, -0-(3-6C-heterocyclyl), -O-heteroaryl, -0-(1-3C-alkyl)-heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, NHC(0)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl,

wherein said group is sometimes substituted, one or more times identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-6C-heterocyclyl,

aril,

R 4 is phenyl which is sometimes substituted one, two or three times, identically or differently,

with a halogen atom;

R5 is hydrogen, 1-3C-alkyl,

R6 is hydrogen, 1-3C-alkyl,

R8 is hydrogen, 1-3C-alkyl which is sometimes substituted with hydroxy,

R9 is hydrogen, 1-3C-alkyl,

R10 is hydrogen, 1-3C-alkyl,

R11 is hydrogen, 1-3C-alkyl,

X,Y is CH2;

n is 0,1,2;

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the present invention relates to compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(0)OR8, NHC(0)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-Alkyl, 1-3C-Alkoxy, -C(O)OR10, 3-6-Cycloalkyl, 3-6C-Heterocyclyl, Aryl,

R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHC(0)(1-3C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-3C-alkyl, - S(0)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-Alkoxy, 3-6C-Cycloalkyl, Aryl, Heteroaryl, -(1-3C-Alkyl)-Aryl, -(1-3C-Alkyl)-Heteroaryl, -O-(3-6C-Cycloalkyl), -O-Aryl, -O-(3-6C-Heterocyclyl), -O

-heteroaryl, -0-(1-3C-alkyl)-heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, - NHS(0)2R11, 3-6C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)0R8, C(0)(1-3C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-3C-alkyl, -S(0)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy 3-6C-cycloalkyl, aryl, heteroaryl, - (1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -0-(3-6C-cycloalkyl), -O-aryl, -0-(3-6C-heterocyclyl), -O-heteroaryl, -0-(1-3C-alkyl)-heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, NHC(0)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group is sometimes substituted, once or more, identically or differently, with a substituent selected from: hydroxy, halogeno, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-6C-heterocyclyl, aryl,

R 4 is phenyl which is sometimes substituted one, two or three times, identically or differently,

with a halogen atom;

R5 is hydrogen, 1-3C-alkyl,

R6 is hydrogen, 1-3C-alkyl,

R8 is hydrogen, 1-3C-alkyl which is sometimes substituted with hydroxy,

R9 is hydrogen, 1-3C-alkyl,

R10 is hydrogen, 1-3C-alkyl,

R11 is hydrogen, 1-3C-alkyl,

X, Y is CH2;

n is 0,1,2;

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the present invention relates to compounds of formula (I) according to claim 1, wherein

R1 is OR7;

R2 is hydrogen,

R3 is C(0)NR8R9, C(0)OR8, halogen, 1-6C-alkyl, 1-6C-alkoxy,

R 4 is phenyl which is sometimes substituted one, two or three times, identically or differently,

with a halogen atom;

R5 is hydrogen, 1-6C-alkyl,

R6 is hydrogen, 1-6C-alkyl,

R7 is 1-4C-haloalkyl,

R8 is hydrogen, 1-6C-alkyl,

R9 is hydrogen, 1-6C-alkyl,

R10 is hydrogen, 1-6C-alkyl,

R11 is hydrogen, 1-6C-alkyl,

X,Y is CH2;

n is 0,1,2;

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, 1-4C-alkoxy,

R2 is hydrogen,

R3 is C(0)NH2, C(0)OR8, halogen, 1-4C-alkyl, 1-4C-alkoxy,

R 4 is phenyl which is sometimes substituted one, two or three times, identically or differently,

with a halogen atom;

R5 is hydrogen, 1-4C-alkyl,

R6 is hydrogen, 1-4C-alkyl,

R7 is 1-4C-haloalkyl,

R8 is hydrogen, 1-4C-alkyl,

R9 is hydrogen, 1-4C-alkyl,

R10 is hydrogen, 1-4C-alkyl,

R11 is hydrogen, 1-4C-alkyl,

X,Y is CHa

n is 0,1,2;

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the present invention are compounds of formula (I) wherein

R1 is hydrogen, methoxy, ethoxy,

R2 is hydrogen,

R3 is C(0)NH2, C(0)OR8, 1-3C-alkyl, bromine, methoxy, ethoxy,

R 4 is phenyl which is sometimes substituted one, two or three times, identically or differently,

with a halogen atom;

R5 is hydrogen, 1-4C-alkyl,

R6 is hydrogen, 1-4C-alkyl,

R7 is 1-4C-haloalkyl,

R8 is hydrogen, 1-4C-alkyl,

R9 is hydrogen, 1-4C-alkyl,

R10 is hydrogen, 1-4C-alkyl,

R11 is hydrogen, 1-4C-alkyl,

X, Y is CH2

n is 0,1,2;

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the present invention are compounds of formula (I) wherein

R1 is hydrogen, 1-3C-alkoxy,

R2 is hydrogen

R3 is 1-3C-alkyl 1-3C-Alkoxy, halogen, trifluoromethyl, C(0)NH2, COOR8, R4 is phenyl

R8 is hydrogen, 1-4C-alkyl,

X, Y is CH2

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the present invention are compounds of formula (I) wherein

R1 is hydrogen, hydroxyl, amino, methoxy, ethoxy, butoxy, pyridin-3-yl, pyridin-4-yl,

pyrazol-3-yl, 1-methyl-pyrazol-3-yl, imidazol-2-yl, methyl, propyl, -0-(CH2)-0-CH3, -O-CH2-phenyl, -0-CH2-cyclopropyl, -C(0)OCH3, -C(0)-NHCH3, -C(0)-NH2, 4-fluoro-phenyl, -(CH2)2-C(0)OCH3, cyclopropyl. -NH-C(0)CH3,

R2 is hydrogen, methyl,

R3 is hydrogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, -0-CH2-C(0)OCH3, -S-CH3, -SO2-CH3, bromine, chlorine, trifluoromethyl, C(0)NH2, COOH, C(0)OCH3, C(0)OCH2CH3, C(0)NH2, C(0)NHCH3, C(0)N(CH3)2, C(0)NH(CH2)2-OH, -

CH=CH2, 4-fluoro-phenyl, NHC(0)CH3, NHC(0)CF3, NH-SO2-CH3, C(0)CH3,

R4 is phenyl

X, Y is CH2

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the present invention are compounds of formula (I) wherein

R1 is hydrogen, methoxy,

R2 is hydrogen

R3 is methyl, ethyl, methoxy, bromine, trifluoromethyl, C(0)NH2, COOH, C(0)OCH3,

C(0)OCH2CH3,

R4 is phenyl

X, Y is CH2

or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In one aspect of the present invention, the compounds of formula (I), as described above, are selected from the group consisting of:

One aspect of the present invention is the compounds disclosed in the examples for intermediates, particularly the compound of general formula (II) shown below in Scheme 1, used for their synthesis.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(0)OR8, NHC(0)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3-6-cycloalkyl, 3-6C-heterocyclyl, aryl.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(0)OR8, NHC(0)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, heteroaryl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from:

halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3-6-cycloalkyl, aryl.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(0)OR8, NHC(0)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-Alkyl, 1-3C-Alkoxy, -C(O)OR10, 3-6-Cycloalkyl, 3-6C-Heterocyclyl, Aryl.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(0)OR8, NHC(0)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-Alkyl, 1-3C-Alkoxy, -C(O)OR10, 3-6-Cycloalkyl, 3-6C-Heterocyclyl, Aryl.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R 1 is hydrogen, -C(O)NH(1-3C-alkyl), -C(O)NH 2 or a group selected from 1-6C-Alkoxy, heteroaryl which are sometimes substituted with 1-3C-Alkyl, 1-3C-Alkoxy.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R 1 is 1-6C-Alkoxy, preferably 1-4-Alkyloxy, especially methoxy.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein R 2 is hydrogen.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, -S(0)2NR5R6, or a group selected from 1-6C-alkyl, 1-6C-alkoxy. 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -0-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), - O-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -Ot(1-6C-alkyl)-aryl, NHC(0)(1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl,

wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from:

hydroxy, halogen, 1-6C-alkyl, i-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-7C-heterocyclic, aryl. Another aspect of the present invention is a compound of formula (I) according to claim 1, wherein R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHS(0)2R11, NHC(0)NHR1j1, -S(0)n-1-3C-alkyl, -S(0)2NR5R6 or a group which is selected from 1-3C-alkyl, 1-3C-alkyl, and 3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -O-(t-6C-cycloalkyl), -O-aryl, -0-(3-6C-heterocyclyl), -O-heteroaryl, -O-(1-3C-alkyl)-heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, NHC(0)(1-3C-alkyl, 2-3C-alkenyl, 2-3C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-Haloalkyl, 1-3C-Alkoxy, -NR8R9, Cyano, - C(O)NR8R9, -C(O)OR10, -NHqO)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-6C-Heterocyclyl, Aryl.

Another aspect of the present invention relates to compounds of formula (I) according to claim 1, wherein

R3 is hydrogen, hydroxy, amino, br<)m, methoxy, ethoxy, butoxy, pyridin-3-yl, pyridin-4-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl, imidazol-2-yl, methyl, propyl, -0-(CH2)-0-CH3, -0-CH2-phenyl, -0-CH2-cyclopropyl, -C(O)H3, -C(0)-NHCH3, -C(0)-NH2, 4-fluoro-phenyl, -

(CH2)2-C(0)OCH3, cyclopropyl, -NH|-C(0)CH3.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R3 is 1-4C-alkyl, C00R8, (C0)NH2, 1-4C-Alkoxy, halogen, and especially methyl, ethyl,

trifluoromethyl, aminocarbonyl, methoxy, methoxycarbonyl, ethoxycarbonyl, COOH, bromine.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R 3 is NR 8 R 9 , -C(O)OR 10 , -C(O)NR 8 R 9 .

In another embodiment of the aforementioned aspects, the present invention relates to compounds of formula (I) according to claim 1, wherein R 4 is an unsubstituted phenyl radical.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein

R 8 is hydrogen, 1-4C alkyl, and especially hydrogen or 1-2C-alkyl.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein n is 0 or 2.

Another aspect of the present invention is the compounds of formula (I) according to claim 1, wherein R1 is selected from the following groups: hydrogen, hydroxy, NR5R6, CO(NR8R9), C(0)OR8, NHC(0)(1-6C-alkyl), or is a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, wherein said the group is sometimes substituted, once or more, identically or differently, with a substituent selected from: halogen, 1-3C-alkyl, 1-3C-alkoxy, - C(O)OR10, 3-6-cycloalkyl, 3-6C-heterocyclyl, aryl,

and R3 is selected from

hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-3C-alkyl, -S(0)2NR5R6 or from the group selected from 1-3C-alkyl, 1-3C-alkoxy 3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -0-(3-6C-cycloalkyl), -O-aryl, -0-(3-

6C-heterocyclyl), -O-heteroaryl, -0-(1-3C-alkyl)-heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, NHC(0)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group is sometimes substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-6C-heterocyclyl, aryl.

Another aspect of the present invention are compounds of formula (I) according to claim 1, wherein R 1 is selected from the following groups: hydrogen, -C(0)NH(1-3C-alkyl), -C(0)NH 2 or is a group selected from 1-6C-alkoxy, heteroaryl sometimes substituted with 1-3C-alkyl, 1-3C-alkyl, and R 3 is -C(O)NR8R9.

Another aspect of the present invention is the compounds of formula (I) according to claim 1, wherein R1 is not selected from the following groups: hydrogen, -C(0)NH(1-3C-alkyl), -C(0)NH2 or is a group selected from 1-6C-alkoxy, heteroaryls which are sometimes substituted with 1-3C-alkyl, 1-3C-alkoxy, and R3 is NR8R9.

Another aspect of the present invention is the compounds of formula (I) according to claim 1, wherein R1 is selected from the following groups: hydrogen, -C(0)NH(1-3C-alkyl), -C(0)NH2 or is a group selected from 1-6C-alkoxy, heteroaryls which are sometimes substituted with 1-3C-alkyl, 1-3C-alkoxy, and R3 is -C(O)OR10.

Another aspect of the present invention is the compounds of formula (I) according to claim 1, wherein R1 is selected from the following groups: hydrogen, -C(0)NH(1-3C-alkyl), -C(0)NH2 or is a group selected from 1-6C-alkoxy, heteroaryl sometimes substituted with 1-3C-alkyl, 1-3C-alkyl, and R3 is 1-4C-alkyl, COOR8, (CO)NH2, 1-4C-Alkoxy, halogen, and especially methyl, ethyl, trifluoromethyl, aminocarbonyl, methoxy, methoxycarbonyl, ethoxycarbonyl, COOH, bromine.

Definitions

"1-6C-alkyl" is a straight or branched alkyl group having 1 to 6 carbon atoms. Examples are methyl, ethyl, n propyl, iso-propyl, n butyl, iso-butyl, sec-butyl and tert-butyl, pentyl, hexyl, preferably 1-4 carbon atoms (1-4C-alkyl), better 1-3 carbon atoms (1-3C-alkyl). Other alkyl constituents mentioned herein having a different number of atoms will be defined as just described taking into account the different length of their chains. When "alkyl" is part of a constituent consisting of "alkyl" together with another component, the definition of "alkyl" from a moment ago also applies.

The term "1-6C-alkenyl" should be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, containing one or more double bonds, and having 2, 3, 4, 5 or 6 carbon atoms, and especially 2 or 3 carbon atoms ("2-3C-alkenyl"), it being understood that in the case where said alkenyl group contains more than one double bond, then said double bonds can be isolated from each other, or conjugated to each other. Said alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-l-enyl, (Z)-penM-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-l-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylprop-1-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-1-methylbut-2-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, l-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-3-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, (Z)-2-methylpent-1-enyl. (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl -ethylbut-1 -enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyi, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, but-1,3-diene. penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl. In particular, said group is vinyl or allyl.

The term "2-6C-alkynyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group containing one or more triple bonds, and containing 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("2-3C-alkynyl"). Said C2-C6-alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylbut-2-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. In particular, said alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl.

NR5R6 represents "amino" as well as "mono- or di-1-6C-alkylamino" radicals which, apart from the nitrogen atom, contain, independently, one or two of the previously mentioned 1-6C-alkyl radicals. Examples are methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, methyl(ethyl)amino and diisopropylamino radicals. The same description applies to any NRxRy residue mentioned in the claims or specification.

"Aryl" represents a mono- or bicyclic aromatic carbocyclic radical having, as a rule, 6 to 10 carbon atoms; for example phenyl or naphthyl. Phenyl is preferred.

The term <n->(1-6C-alkyl)-aryl" represents an aryl radical, as defined above, which is attached to the rest of the molecule via a straight or branched alkyl chain, preferably -(CH2)-aryl, or -(CH2CH2)-aryl. Benzyl is particularly preferred.

The term "aryloxy" or "-O-aryl" represents the same aryl moieties as defined for the term aryl wherein the ring is attached to the remainder of the molecule via an oxygen atom.

The term "-O-(1-6C-alkyl)-aryl" represents the same aryl moieties as defined by the term aryl wherein said ring is attached to the rest of the molecule via an -O-(1-6Calkyl) linker. Preferred -O-(1-6Calkyl) linkers in this context are -O-(CH2)-, or -O-(CH2CH2)-. Benzyloxy is particularly preferred.

"Halogen" within the scope of this invention is iodine, bromine, chlorine or fluorine, and preferably "halogen" within the meaning of this invention is chlorine or fluorine, but if halogen is used as a leaving group during the synthesis, then bromine or iodine is preferred.

"1-4C-Haloalkyl", which may also be defined as any alkyl radical substituted one or more times with a halogen, is a straight or branched alkyl group having 1 to 4 carbon atoms wherein at least one hydrogen is substituted with a halogen atom. Examples are chloromethyl or 2-bromoethyl. For a partially or fully fluorinated C1-C4-alkyl group, the following partially or fully fluorinated groups are contemplated, for example: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, and penta-fluoroethyl, wherein fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, or 1,1,1-trifluoroethyl are preferred. Partially or fully fluorinated C1-C4-alkyl groups are considered to be covered by the term 1-4C-haloalkyl.

"1-6C-Alkoxy" represents radicals which, in addition to oxygen atoms, contain straight or branched alkyl radicals having 1 to 6 carbon atoms. Examples that may be mentioned are hexoxy, pentoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals, with methoxy, ethoxy, propoxy, isopropoxy being preferred.

"3-7C-Cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl.

"3-7C-Cycloalkyloxy" or <n->O-(3-7C-cycloalkyl)" means cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, preferably cyclopropyloxy.

The term "heteroaryl" represents a monocyclic 5- or 6-membered aromatic heterocycle including, but not limited to, 5-membered heteroaryl radicals, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl. (1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or 1,2,4-thiadiazolyl) and oxadiazolyl (1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl), as well as 6-membered heteroaryl radicals, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, and preferred 5- or 6-membered heteroaryl radicals are furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. Preferred 5- or 6-membered heteroaryl radicals are furan-2-yl, thien-2-yl, pyrrole-2-yl, thiazolyl, oxazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazoyl, pyridin-2-yl, pyridin-4-yl, pyrimidine-2-yl, pyridin-4-yl, pyrazin-2-yl, or pyridazin-3-yl.

The term "-(1-6C-alkyl)-heteroaryl" represents a heteroaryl radical, as defined above, which is attached to the rest of the molecule by means of a straight or branched alkyl chain, preferably -(CH2)-heteroaryl, or -(CH2CH2)-heteroaryl, where -

(CH 2 )-heteroaryl is particularly preferred.

The term "heteroaryloxy" or "-O-heteroaryl" refers to the same heteroaryl moieties as defined by the term heteroaryl, wherein the ring is attached to the remainder of the molecule by an oxygen atom.

The term "-O-(1-6C-alkyl)-heteroaryl" means the same heteraryl moieties as defined by terminal heteroaryl, wherein the ring is attached to the rest of the molecule via an -O-(1-6Calkyl) linker.

The term "-0-(1-6C-alkyl) linker" can vary according to the needs of this invention and refers to an alkylene chain having from 1-6, 1-5, 1-4, 1-3, 1-2 or 1 carbon atom, and the linker itself can be straight or branched when possible.

"3-7C-Heterocyclyl", or "heterocyclyl" represents a mono- or polycyclic, preferably mono- or bicyclic, preferably monocyclic, non-aromatic heterocyclic radical containing 4 to 10, preferably 4 to 7 ring atoms, and up to 3, preferably up to 2, hetero-atoms and/or hetero-groups from the series comprising N, O, S, SO, SO2. Heterocyclyl radicals may be saturated or partially unsaturated and, unless otherwise stated, may sometimes be substituted, one or more times, identically or differently, with a substituent selected from: 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, hydroxy, fluoro, wherein 1-4C-alkyl may sometimes be additionally substituted with hydroxy.

Particularly preferred heterocyclic radicals are 4- to 7-membered monocyclic

saturated heterocyclyl radicals having up to two heteroatoms from the series comprising 0, N and S. The following may be mentioned as a preferred example: oxetanyl, tetrahydrofuranyl, azetidinyl, 3-hydroxyazetidinyl, 3-fluoroazetidinyl, 3,3-difluoroazetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, pyrrolinyl, piperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 3-fluoropiperidinyl, 3,3-difluoropiperidinyl, 4-fluoropiperidinyl, 4,4-difluoropiperidinyl, piperazinyl, N-methyl-piperazinyl, N-(2-hydroxyethyl)-piperazinyl, morpholinyl, thiomorphoinyl, azepanyl, homopiperazinyl, N-methyl-homopiperazinyl.

The term "heterocyclyloxy" or -O-heterocyclyl" means the same heterocyclic radicals as defined by the term heterocyclyl, wherein the ring C atom is attached to the rest of the molecule through an oxygen atom. Preferred heterocyclic radicals are unsubstituted, or sometimes may be substituted on the ring nitrogen atom with a substituent selected from: 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-Alkoxy.

The term "-O-(1-6C-alkyl)-heterocyclyl" means the same heterocyclyl moieties as defined by the term heterocyclyl, wherein the ring is attached to the rest of the molecule via an -O-(1-6Calkyl) linker. In one aspect of the present invention, heterocyclic residues containing one or more ring nitrogen atoms are preferably attached to an -O-(1-6-alkyl) linker via one of said nitrogen atoms.

The term -(1-6C-alkyl)-heterocyclyl denotes the same heterocyclyl moieties as defined under the term heterocyclyl above, wherein the ring is attached to the remainder of the molecule via a -(1-6C-alkyl) linker.

NH(CO)1-6C-alkyl or NH(CO)R11 group includes for example NH(CO)CH3, NH(CO)C2H5, NH(CO)C3H7, NH(CO)CH(CH3)2.

The NHS(0)2R11 group includes for example NHS(0)2CH3, NHS(0)2C2H5, NHS(0)2C3H7, NHS(0)2CH(CH3)2.

The NH(C0)NHR11 group includes for example NHC(0)NHCH3, NHC(0)NHC2H5.

A C(O)NR8R9 group includes, for example, C(0)NH2, C(0)N(H)CH3, C(0)N(CH3)2, C(0)N(H)CH2CH3, C(0)N(CH3)CH2CH3 or C(0)N(CH2CH3)2. In the case of -NR 8 R 9 , when R 8 and R 9 together with the nitrogen atom to which they are attached form a 3-6C-heterocyclic ring, the term "3-6C-heterocyclic ring" is defined above.

The C(0)OR8 group includes for example C(0)OH, C(0)OCH3, C(0)OC2H5, C(0)C3H7, C(0)CH(CH3)2, C(0)OC4H9, C(0)OC5H11, C(0)OC6H13; whereby in C(0)0(1-6Calcyl) the alkyl part can be straight or branched.

Constituents which are sometimes substituted as specified herein may be substituted, unless otherwise specified, one or more times, independently of each other at any possible position. When any variable occurs more than once in any constituent, each definition is independent.

In the case of R 1 , R 2 or R 3 it should be understood that groups selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl may sometimes be substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-Alkoxy, - NR8R9, cyano, -C(O)NR8R9, -C(O)OR10, -NHC(0)R11, -NHS(0)2R11. Preferred groups are -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O-(1-6C-alkyl)-heteroaryl, -O-(1-6C-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-alkyl)-aryl.

The heteroaryl, or heterocyclic, groups mentioned herein may be substituted with their own substituents or parent molecular groups, unless otherwise stated, at any possible position, such as for example at any suitable carbon or ring atom or ring nitrogen atom. Analogously, it should be understood that any heteroaryl or heterocyclyl group may be attached to the rest of the molecule via any suitable atom in accordance with the laws of chemistry. Unless otherwise stated, any heteroatom from a heteroaryl ring with unsaturated valences mentioned herein is considered to have hydrogen atoms in order to satisfy said valencies. Unless otherwise stated, rings containing nitrogen atoms of the amino- or imino-type ring (-N=), which can be quaternized, preferably need not be quaternized on said nitrogen atoms of the amino- or imino-type ring by means of said substituents or parent molecular groups.

Salts of compounds according to the present invention include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmacy.

One aspect of the present invention is the salts of compounds according to the present invention including all inorganic and organic acid addition salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts commonly used in pharmacy. Another aspect of this invention are salts with di- and tricarboxylic acids.

Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, sulfamic acid salts, formates, acetates, propionates, citrates, D-gluconates, benzoates, 2-(4-hydroxybenzoyl)-benzoates, butyrates, salicylates, sulfosalicylates, lactates, maleates, laurates, malates, tumarates, succinates, oxalates, malonates, pyruvates, acetoacetates, tartrates, stearates, benzenesulfonates, toluenesulfonates, methanesulfonates, trifluoromethanesulfonates, 3-hydroxy-2-naphthoates, benzenesulfonates, naphthalene sulfonates and trifluoroacetates.

Examples of salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine, ammonium salts, which are sometimes derived from NH3 or organic amines having from 1 to 16 C-atoms such as, for example, salts of ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and guanidinium.

Said salts include water-insoluble salts and especially water-soluble salts.

According to those skilled in the art, the compounds of formula (I) according to the present invention, as well as their salts, may contain, for example when isolated in crystalline form, various amounts of solvents. Therefore, the scope of this invention includes all solvates, and especially all hydrates of compounds of formula (I) according to this invention, as well as all solvates, and especially hydrates of salts of compounds of formula (I) according to this invention.

The term "combination" in this invention is used as a term known to those skilled in the art and may be present as a fixed combination, a non-fixed combination, or a kit of parts.

A "fixed combination" in the present invention is known to those skilled in the art and is defined as a combination in which said first active ingredient and said second active ingredient are present together in one unitary dose or in one entity. One example of a "fixed combination" is a pharmaceutical composition in which said first active ingredient and said second active ingredient are present in admixture for simultaneous administration, such as a formulation. Another example for a "fixed combination" is a pharmaceutical combination in which said first active ingredient and said second active ingredient are present in one unit without mixing with each other.

A non-fixed combination or "kit of parts" is used in the present invention as is already known to those skilled in the art, and is defined as a combination in which said first active ingredient and said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit of parts is a combination in which said first active ingredient and said second active ingredient are present separately. The components of a non-fixed combination or kit composed of parts may be administered separately, sequentially, simultaneously, side by side, or chronologically.

The term "cancer chemotherapeutic agents" includes, but is not limited to, (i) alkylating/carbamylating agents such as Cyclophosphamide (Endoxan®), Ifosfamide (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan (Alkeran®), or Chloroethylnitrosourea (BCNU); (ii) platinum derivatives such as cis-platinum (Platinex® BMS), oxaliplatin (Eloxatin®), satraplatin or carboplatin (Kabroplat® BMS); (iii) antimitotic agents/tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Paclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as well as their new formulations and conjugates (such as the nano-particle formulation Abraksan® with albumin-bound paclitaxel), epothilones such as Epothilone B (Patupilon®), Azaepotilone (Ixabepilon®) or Sagopylon; (iv) topoisomerase inhibitors such as anthracyclines (eg Doxorubicin/Adriblastin®), epipodophyllotoxin (eg Etoposide/Etopofos®) and camptothecin and camptothecin analogues (eg Irinotecan/Camptosar® or Topotecan/Hikamtin®); (v) pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®), Arabinosylcytosine/Cytarabine (Alexan®) or Gemcitabine (Gemzar®); (vi) purine antagonists such as 6-mercaptopurine (Puri-Netol®), 6-thioguanine or fludarabine (Fludara®) and (vii) folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®).

The term "targeted anticancer agent" includes, but is not limited to, (i) kinase inhibitors such as, for example, Imatinib (Glivec®), ZD-1839/Gefitinib (Iresa®), Bay43-9006 (Sorafenib, Nexavar®), SU1 1 248/Sunitinib (Sutent®), OSI-774/

Erlotinib (Tarceva®), Dasatinib (Sprledenul®), Lapatinib (Tikerb®), or, also see below, Vatalanib, Vandetanib (Zactima®), or Pazopanib; (ii) proteasome inhibitors such as PS-341/Bortezumib (Velkad®); (iii) histone deacetylase inhibitors like SAHA (Zolinza®), PXD101, MS275, MGCD0103, Depsipeptide/FK228, NVP-LBH589, Valproic acid (VPA), CRA/PCI 24781, ITF2357, SB939 and butyrate, (iv) heat shock protein 90 (hsp90) inhibitors like 17-allylaminogeldanamycin (17-AAG) or 17-dimethylaminogeldanamycin (17-DMAG); (v) vascular targeting agents (VTA) such as combretastin A4 phosphate or AVE8062/AC7700 and anti-angiogenic drugs such as VEGF antibodies such as Bevacizumab (Avastin®), or KDR tyrosine kinase inhibitors such as PTK787/ZK222584 (Vatalanib®) or Vandetanib (Zaktima®) iii Pazopanib; (vi) monoclonal antibodies such as Trastuzumab (Herceptin®), Rituximab (MabTera/Rituxan®), Alemtuzumab (Kampat®), Tositumomab (Beksxar®), C225/Cetuximab (Erbitux®), Avastin (see above) or Panitumumab (Vectibix®) as well as mutants and conjugates of monoclonal antibodies, for example Gemtuzumab ozogamicin (Milotarg®) or Ibritumomab tiuxetan (Zevalin®), and antibody fragments; (vii) therapeutics based on oligonucleotides such as G-3139/Oblimersen (Genasens®) or the DNMT1 inhibitor MG98; (viii) Toll-like receptor/TLR 9 agonists such as Promun®, TLR 7 agonists such as Imiquimod (Aldara®) or Isatoribine and their analogs, or TLR 7/8 agonists such as Resiquimod as well as RNA immunostimulators such as TLR 7/8 agonists; (ix) protease inhibitors; (x) hormonal therapeutics such as anti-estrogens (eg Tamoxifen or Raloxifene), anti-androgens (eg Flutamide or Kasodex), LHRH analogues (eg Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors (eg Femara, Arimedex or Aromasin).

Other "targeted anticancer agents" include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as 5-Aza-2'-deoxycytidine (Decitabine, Dakogen®) and 5-azacytidine (Vidaza®), alanosine, cytokines such as interleukin-2, interferons such as interferon ac2 or interferon-Y, bcl2 antagonists (eg, ABT-737 or analogs), receptor agonists for tumor necrosis, such as TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists (eg TRAIL receptor agonists such as mapatumumab or lexatumumab).

Specific examples of anticancer agents include, but are not limited to, 1311-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabine, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bianthrene, bleomycin, bortezomib, busereiin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, chrysantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epithiostanol, epoetin alfa, epoetin beta, heptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxime, goserelin, histamine dihydrochloride, histrelin, hydroxyurea, seme 1-125, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, iomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostan, mercaptopurine, methotrexate, methoxysalen, methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatinum, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatinum, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, polyglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, hinagolide, radium-223 chloride, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, sisofiran, sobusoxan, sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, timalfasin, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trophosphamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozol, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

A special aspect of the present invention are combinations comprising at least one compound according to claim 1 and at least one anticancer drug selected from the group consisting of Ancestim, atrigel-leuprolide, axitinib, Bacillus Calmette-Guerin (BCG)-Tice, bosutinib, brentuximab vedotin, brivanib alaninate, Kervarix, cinacalcet hydrochloride, crizotinib, cytarabine oxphosphate, diethylstilbestrol, elution beads doxorubicin, enzastaurin hydrochloride, etoposide phosphate disodium salt, floxuridine, fludeoxyglucose (18F), Gardasil, histrelin acetate, icotinib hydrochloride, ingenol mebutate, interferon alfa-2A, interferon alfa-2b, interferon alfa-n1, interferon alfa, interferon gamma-n1, ketoconazole, leucovorin/LIFT, leuprolide acetate depot, levothyroxine sodium, liposomal cytarabine, liposomal daunorubicin, liposomal doxorubicin, M-Vax, MDV-3100, midostaurin, minocycline hydrochloride, motesanib diphosphate, muromonab-CD3, oblimersen sodium, octreotide acetate, omacetaxine mepesuccinate, ombrabulin hydrochloride, paclitaxel nanoparticles, paclitaxel polyglumex, PEG-liposomal doxorubicin hydrochloride, pilocarpine hydrochloride, pixantrone maleate, rapamycin, ridaforolimus, ruboxistaurin mesylate hydrate, ruxolitinib phosphate, thyrotropin alfa, trimetrexate glucuronate, VAL-083, vesnarinone, vincristine TCS, virulisin, zotarolimus, AZD-8055, BEZ-235, BGT-226, BKM-120, CAL-101, CC-223, GDC-0980, GSK-2110183, GSK-2636771, OSI-027, perifosine, PF-04691502, pictrelisib, PX-866, triciribine phosphate, UCN-01, XL-147, XL-765, ARRY-162, AS-703026, E-6201, selumetinib, trametinib dimethyl sulfoxide.

The compounds of the present invention and their salts may exist in the form of tautomers included in the embodiments of the present invention.

The compounds of this invention may, depending on their structure, exist in different stereoisomeric forms. Said forms include configurational isomers or sometimes conformational isomers (enantiomers and/or diastereomers including those of atropisomers). This invention therefore includes enantiomers, diastereomers as well as mixtures thereof. From the mentioned mixtures of enantiomers and/or diastereomers, the pure stereoisomeric forms can be isolated using methods known in the art, preferably methods such as chromatography, especially high pressure liquid chromatography (HPLC) using an achiral or chiral phase. The present invention further includes all mixtures of the stereoisomers mentioned above regardless of isomer, including racemates. Some compounds and salts according to this invention may exist in various crystalline forms (polymorphs) that fall within the scope of this invention.

Furthermore, derivatives of compounds with formula (I) and their salts are disclosed, which are converted into a compound with formula (I) or its salt in a biological system (bioprecursors or pro-drugs).

The mentioned biological system is for example a mammal, especially a human being. The mentioned bioprecursor is, for example, converted into a compound with formula (I) or into one of its salts with the help of metabolic processes.

Intermediates used for the synthesis of the compounds of claims 1-5 as described below, as well as their use for the synthesis of the compounds of claims 1-5, are disclosed. Preferred intermediates are Exemplary Intermediates as disclosed below.

The compounds of the present invention can be prepared as follows.

The compounds of the present invention may be prepared according to the following scheme,

wherein X, Y, R 1 , R 2 , R 3 and R 4 have the meanings previously defined, wherein R x R y is R 6 , or some protecting group; Hal is halogen, preferably M is Mg-Hal, Zn-Hal, or Li.

Compounds of general formula (I) can be prepared from compounds of general formula (II). Rx can sometimes be R6, or some protecting group, or other such precursor that requires additional manipulation.

The use of amine protecting groups in organic synthesis is well known to those skilled in the art. Amine protecting groups include, but are not limited to: • carbamate protecting groups, including but not limited to methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate, (Fmoc), tert-butyl carbamate (BOC), allyl carbamate, and benzyl carbamate (CBZ) including benzyl carbamates that are substituted on the phenyl ring, • amide protecting groups, including but not limited to N-formyl amide, and N-acetyl amide, • N-benzyl amine protecting groups, including N-benzyl amines which are substituted on the phenyl ring.

When Rx and Ry of a compound of formula (I) are both hydrogen, Rx of a compound of formula (II) may be a protecting group and Ry of a compound of formula (II) may be hydrogen, the same protecting group as Rx, or a different protecting group, or Rx and Ry may be joined to form a cyclic imide protecting group, such as an N-phthaloyl protecting group.

The amine protecting group can be reacted with a suitable reagent to remove said protecting group and replace it with hydrogen. Such suitable reagents include, but are not limited to: • acidic reagents, which include, but are not limited to, hydrochloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, boron tribromide; acidic reagents can be used to remove tert-butyl carbamate, N-formyl amide, or N-acetyl amide or protecting groups. • base reagents, which include, but are not limited to, lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium carbonate, ammonium hydroxide; basic reagents can be used to remove protecting groups such as methyl carbamate, 9-fluorenyl carbamate, ethyl carbamate, N-formyl amide, or N-acetyl amide. • nucleophilic reagents, including but not limited to lithium iodide, sodium iodide, potassium iodide, trimethylsilyl iodide, hydrazine, wherein nucleophilic reagents can be used to remove protecting groups such as benzyl carbamate, N-formyl amide, N-acetyl amide, or N-phthaloyl. • metal-mediated reagents, including but not limited to nickel, palladium, platinum reagents that can be used to deprotect allyl carbamates. • reducing reagents, including, but not limited to, sodium in ammonia, or a combination of hydrogen sources, such as, but not limited to, hydrogen gas, formic acid, or formic acid salts, and metal reagents, including, but not limited to, nickel, palladium, platinum reagents; reducing agents can be used to remove protecting groups such as 9-fluorenylmethyl carbamate, benzyl carbamate, or N-benzyl amine.

For example, Rx in compounds of general formula (II) may be a protecting group such as a Boe group, -CO(OtBu). The preparation of compounds of general formula (I) can thus be achieved by using a suitable deprotection reaction, as in the case of the Boe group, under acidic reaction conditions, for example, with a solution of 4M hydrochloric acid in dioxane or trifluoromethanesulfonic acid, in some suitable solvent, such as for example DCM and methanol, at ambient temperature. Additional conditions for deprotection of the Boe group, or other protecting groups that may be suitable for blocking amino-functionality in compounds of general formula (II), including their synthesis and deprotection, can be found in, for example, T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000. Similarly, when Ry is not H, then Ry is some protecting group, such as when Rx and Ry together form a cyclic protecting group such as phthalamide.

Furthermore, the compounds of the general formula (II) may contain a functionality that can be further modified, which enables the introduction of the desired functionality into the R1, R2 or R3 groups. Such transformations include oxidations, reductions, nucleophilic substitutions, electrophilic substitutions, radical reactions, or metal-mediated reactions such as metal-assisted cross-coupling reactions, such as for example Suzuki, Stille, or Heck reactions, and the like. Similarly, compounds of general formula (I) may also be modified in such a way as to provide additional compounds according to the present invention, provided that said transformations do not cause undesired side effects on the -NHR6 group.

Thus, an additional aspect of the present invention is a process for producing a compound of general formula (I) according to claim 1 by reacting a compound of general formula (II)

where

R 1 -R 4 have the meaning specified in claim 1, a

Rx,Ry are R6, or some protecting group,

wherein the transformation into the compound with the general formula (I) is achieved with the help of applying some suitable deprotection reaction, and the already mentioned protecting groups can be used.

Another aspect of the present invention is a process, as disclosed a moment ago, whereby subsequent to or prior to the deprotection step, additional modifications may be made that allow the introduction of some desired functionality into the R1, R2 or R3 groups.

Compounds of the general formula (II) can be prepared from an intermediate ketone of the general formula (III) and a heterocyclic amine of the general formula (IV) by applying some appropriate cyclization reaction. For example, compounds of general formula (II) can be prepared by reacting (III) and (IV) in a suitable solvent, such as, for example, DMF or ethanol, at elevated temperatures of 50° C. to 150° C. The use of basic additives such as a tertiary amine, for example, triethylamine, can be useful.

Compounds of general formula (IV) are commercially available, can be prepared using the procedures described in the aforementioned examples, can be prepared using known procedures, or can be prepared using procedures analogous to those known to a person skilled in the art.

Compounds of general formula (III) can be prepared from ketones of general formula (V) by applying some suitable halogenation reaction. For example, in the case where the halogen is Br, a suitable bromination reaction can be applied, such as for example reacting a ketone of general formula (V) with pyridinium hydrobromide perbromide in a suitable solvent, such as THF, at suitable temperatures, such as for example from 0°C to ambient temperature.

Compounds of general formula (V) can be prepared from compounds of general formula (VI) by known procedures, such as addition of appropriate organometallic reagents (VII), in a suitable solvent, such as ethereal solvents, for example THF, at low temperature, for example from -78°C to -10°C, preferably from -30°C to -10°C. Preferred organometallic reagents are for example organomagnesium reagents in which M is -MgCl or -MgBr, preferably -MgCl.

Compounds of general formula (VI) can be prepared from compounds of general formula (VIII) using known procedures, such as a palladium-catalyzed cyanation reaction using a suitable catalyst such as tetrakis(triphenylphosphine)palladium(0)[Pd(PPh3)4], a suitable cyano source such as zinc dicyanide, a suitable solvent such as DMF, where dry DMF may be useful, and at elevated temperatures, such as the boiling point of the solvent, preferably at 80°C.

Compounds of general formula (VIII) and (IX) are commercially available, and may be prepared by methods described below, may be prepared by known methods, or may be prepared by methods analogous to those known to those skilled in the art.

Compounds of formula (II) are disclosed in which specifically Rx is a Boe group, - CO(OtBu), and Ry is hydrogen.

Another aspect of the present invention is a process for the production of a compound of the general formula (I), characterized in that the compound of the formula

wherein R1-R4, X and Y have the meaning according to claim 1 and Rx is R6 or a protecting group; Ry is hydrogen or a protecting group, or Rx and Ry together, or Y and Rx

together, they can form a cyclic protecting group, Hal is a halogen,

is reacted with a solution of 4M hydrochloric acid in dioxane or trifluoromethanesulfonic acid, in a suitable solvent, such as for example DCM and methanol, at ambient temperature resulting in the formation of a compound of formula (I)

Thus, another aspect of the present invention is the use of intermediates of formula (II) for the preparation of compounds of formula (I).

One preferred aspect of the present invention is a process for the preparation of the compounds of claims 1-5 in accordance with the Examples.

One skilled in the art knows that when there are numerous reactive centers on the starting or intermediate compounds, it may be necessary to temporarily block one or more reactive centers with protecting groups in order to allow the reaction to occur specifically at the desired reaction center. A detailed description of the use of a large number of proven protecting groups can be found, for example, in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000.

The compounds of the present invention are isolated and purified in a manner known per se, for example by distillation of the solvent in vacuo and recrystallization of the residue obtained from a suitable solvent or by subjecting it to one of the usual purification procedures, such as chromatography on a suitable support. Furthermore, preparative HPLC (reverse phase) of compounds of the present invention, which possess sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present invention that is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention that is sufficiently acidic, an ammonium salt for example. Salts of this type can be transformed into the free base or free acid by a number of procedures known to those skilled in the art, or can be used as salts in appropriate biological assays. Additionally, the drying process during the isolation of compounds of the present invention does not have to completely remove traces of co-solvents, especially such as formic acid or trifluoroacetic acid, in order to obtain solvates or inclusion complexes. One skilled in the art will recognize which solvates or inclusion complexes are acceptable for use in appropriate biological assays. It should be understood that the specific form (eg, salt, free base, solvate, inclusion complex) of a compound of the present invention, which is isolated as described above, is not necessarily the only form in which said compound can be used in a biological assay to quantify a specific biological activity.

Salts of compounds of formula (I) according to the present invention can be obtained by dissolving the free compound in a suitable solvent (for example, a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) containing the desired acid or base, or to which the desired acid or base has been added. Said acid or base can be used to prepare said salt, depending on whether it is a mono- or poly-basic acid or base and depending on which salt is desired, in an equimolar or different quantitative ratio. Said salts are obtained by filtration, re-precipitation, precipitation with a non-solvent for the salt or by evaporation of the solvent. The salts obtained can be converted into free compounds which, in turn, can be converted into the mentioned salts. In this way, pharmaceutically unacceptable salts, which may be obtained, for example, as process products during production on an industrial scale, can be converted into pharmaceutically acceptable salts by means of processes known to one skilled in the art.

Pure diastereomers and pure enantiomers of compounds and salts according to the present invention can be obtained, for example, by means of asymmetric synthesis, by means of

using chiral starting compounds for the synthesis and separation of enantiomeric and diastereomeric mixtures that arise during said synthesis.

Enantiomeric and diastereomeric mixtures can be separated into pure enantiomers and pure diastereomers by methods known to those skilled in the art. Preferably, diastereomeric mixtures are separated by means of crystallization, especially fractional crystallization, or chromatography. Enantiomeric mixtures are separated, for example, by forming diastereomers with some chiral auxiliary agent, resolving the obtained diastereomers and removing said chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids are used in order to separate enantiomeric bases such as for example mandelic acid, while chiral bases can be used in order to separate enantiomeric acids with the help of the formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, with the help of using chiral acids or chiral alcohols as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates can be used to separate enantiomeric mixtures. Alternatively, enantiomeric mixtures can be separated by chromatography using chiral separation columns. Another convenient method for isolating enantiomers is enzymatic separation.

One preferred aspect of the present invention is a process for the preparation of the compounds of claims 1-5 according to the examples.

Sometimes, the compounds of formula (I) can be converted to their salts, or, sometimes, the salts of said compounds of formula (I) can be converted to the free compounds. Appropriate processes are common to those skilled in the art.

Sometimes, compounds of formula (I) can be converted to their N-oxides. The N-oxide can also be introduced with the help of an intermediate. The N-oxides can be prepared by treating a suitable precursor with an oxidizing agent, such as meta-chloroperbenzoic acid, in a suitable solvent, such as dichloromethane, at suitable temperatures, such as from 0° C. to 40° C., with room temperature being generally preferred. Additional suitable processes for the formation of N-oxides are common to those skilled in the art.

Commercial benefit

Compounds of formula (I) and stereoisomers of compounds of formula (I) according to the present invention are hereinafter referred to as compounds of the present invention. Specifically, the compounds of the present invention are pharmaceutically acceptable. The compounds according to the present invention have valuable pharmaceutical properties, which make them commercially useful. Specifically, the mentioned compounds inhibit the Pi3K/Akt pathway and affect cellular activity. The said compounds are therefore expected to be commercially applicable in disease therapies (for example, diseases that depend on excessive Pi3K/Akt activity). Abnormal activity of the PI3K/AKT pathway is a crucial step towards the initiation and maintenance of human tumors, so its inhibition, for example with the help of AKT inhibitors, is considered a valid approach for the treatment of human tumors. For a recent review article see Garcia-Echeverria et al (Oncogene, 2008, 27, 551-5526).

Cellular activity and analogous terms herein are used in a manner known to one skilled in the art, such as, for example, inhibition of phosphorylation, inhibition of cell proliferation, induction of apoptosis or chemosensitization.

Chemosensitization and analogous terms in this invention are used in a manner known to one skilled in the art. These stimuli include, for example, tumor necrosis factor receptor effectors and survival pathways as well as cytotoxic/chemotherapeutic and targeting agents and ultimately radiation therapy. Apoptosis induction and analogous terms according to the present invention are used to identify a compound that carries out programmed cell death in cells contacted with said compound or in combination with other compounds routinely used for therapy.

Apoptosis in the present invention is used in a manner known to those skilled in the art. Induction of apoptosis in cells contacted with said compound of the present invention does not necessarily have to be associated with inhibition of cell proliferation. Preferably, inhibition of proliferation and/or induction of apoptosis is specific to cells exhibiting aberrant cell growth.

Furthermore, the compounds according to the present invention inhibit the action of protein kinase in cells and tissues, which causes a shift towards the dephosphorylated substrate (proteins), and as a functional consequence, for example, there is the induction of apoptosis, cell cycle arrest and/or sensitization to chemotherapeutics and drugs targeting a specific target. In one preferred embodiment, inhibition of the Pi3K/Akt pathway promotes cellular effects, as mentioned above, either alone or in combination with standard cytotoxic drugs or drugs that target a specific target.

Compounds according to the present invention possess anti-proliferative and/or pro-apoptotic and/or chemosensitizing properties. Accordingly, the compounds of the present invention are useful for the treatment of hyperproliferative disorders, and in particular for the treatment of cancer. Accordingly, the compounds of the present invention are useful for inducing an anti-proliferative and/or pro-apoptotic and/or chemosensitizing effect in mammals, such as humans, suffering from hyperproliferative disorders, such as cancer.

The present invention additionally relates to a compound according to the present invention or to a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis, preferably the treatment of (hyper)proliferative diseases and/or disorders that respond to stimulation of apoptosis, which include benign neoplasia and malignant neoplasia, and especially malignant neoplasia, including cancer and the types of tumors disclosed below.

The compounds of the present invention exhibit anti-proliferative and/or pro-apoptotic properties in mammals such as humans due to inhibition of the metabolic activity of tumor cells that are able to survive despite adverse growth conditions such as glucose deprivation, hypoxia or other chemo-stress.

Thus, compounds according to the present invention are useful for treating, ameliorating or preventing diseases with benign or malignant behavior as described herein, such as for example inhibiting cellular neoplasia.

The neoplasia in the present invention is used in a manner known to those skilled in the art. Benign neoplasia is characterized by hyperproliferation of cells, whereby the cells cannot form an aggressive tumor that metastasizes in vivo. On the contrary, malignant neoplasia is characterized by cells that possess numerous cellular and biochemical abnormalities, which are capable of forming a systemic disease, for example, forming tumor metastasis in separate organs.

The compounds of the present invention may preferably be used for the treatment of malignant neoplasia. Examples of malignant neoplasia that can be treated with the compounds of the present invention include solid and hematological tumors. Examples of solid tumors are tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (eg, thyroid gland and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, tumors of the ovary, pancreas, prostate, rectum, urinary system, small intestine, soft tissue, testis, stomach, skin, urethra, vagina and vulva. Malignant neoplasias include hereditary tumors such as retinoblastoma and Wilms tumor. Additionally, malignant neoplasms include primary tumors in said organs and corresponding secondary tumors in separate organs ("tumor metastases"). Examples of hematological tumors are aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma, and T-cell lymphoma. Also included are myelodysplastic syndromes, plasma cell neoplasia, paraneoplastic syndromes, and tumors of unknown primary location as well as AIDS-related malignancies.

In another aspect of the present invention, compounds according to the present invention may preferably be used for the treatment of breast cancer. It should be noted that malignant neoplasia does not necessarily imply the occurrence of metastases in separate organs. Certain tumors have devastating effects in primary organs due to aggressive growth. This can lead to the destruction of tissue and organ structure, which ultimately leads to organ failure and death.

Drug resistance is of great importance for the frequent failure of standard cancer therapeutics. The aforementioned drug resistance is caused by numerous cellular and molecular mechanisms. One aspect of drug resistance is caused by constitutive activation of anti-apoptotic survival signaling with PKB/Akt serving as a key signaling kinase. Inhibition of the Pi3K/Akt pathway results in resensitization to standard or targeted chemotherapeutics. As a consequence, the commercial applicability of the compounds according to the present invention is not limited to the first line treatment of tumor patients. In a preferred embodiment, patients with a tumor showing resistance to anticancer chemotherapeutics or targeted anticancer drugs can also be treated with said compounds during a second or third cycle of treatment. Specifically, compounds according to the present invention can be used in combination with standard chemotherapeutics or targeted drugs with the aim of sensitizing tumors to said agents.

The compounds according to the present invention are suitable for the treatment, prevention or alleviation of diseases of benign or malignant behavior as described above, such as for example benign or malignant neoplasia, especially cancer, and especially cancer that is sensitive to inhibition of the Pi3K/Akt pathway.

This disclosure further includes a method for treating, preventing or alleviating a disease, preferably treating a mammal, including humans, suffering from one of the aforementioned conditions, infirmities, disorders or diseases. This method is characterized in that a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds according to the present invention is administered to a subject in need of such treatment.

This disclosure further includes a method for treating, preventing, or ameliorating diseases responsive to inhibition of the Pi3K/Akt pathway, in a mammal, including a human, preferably treating a disease sensitive to inhibition of the Pi3K/Akt pathway, in a mammal, including a human, comprising administering to said mammal a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds in accordance with the present invention.

This disclosure further includes a method for inhibiting protein kinase activity in cells comprising administering to a patient in need thereof a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds in accordance with the present invention.

This disclosure further includes a method for the treatment of benign or malignant hyperproliferative diseases and/or disorders that respond to the induction of apoptosis, such as for example cancer, especially any of the tumor diseases described herein, in a mammal, wherein said method comprises administering to said mammal a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds in accordance with the present invention.

This disclosure further includes a method for inhibiting cellular hyperproliferation or arresting aberrant cellular growth in a mammal, comprising administering to said mammal a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds in accordance with the present invention.

This disclosure further includes a method for inducing apoptosis during the treatment of benign or malignant neoplasia, particularly cancer, comprising administering to a subject in need a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds in accordance with the present invention.

This disclosure further includes a method for sensitizing a mammal to chemotherapeutics or anticancer agents that target a specific target, comprising administering to said mammal a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds in accordance with the present invention.

This disclosure further includes a method for the treatment of benign and/or malignant neoplasia, particularly malignant neoplasia, particularly cancer, in a mammal, including a human, comprising administering to said mammal a pharmacologically active and therapeutically effective and tolerable amount of one or more compounds in accordance with the present invention.

This disclosure further includes a method for the treatment of solid and hematological tumors, examples of solid tumors being tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (for example, thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, tumors of the ovary, pancreas, prostate, rectum, urinary system, small intestine, soft tissue, testicles, stomach, skin, urethra, vagina and vulva. Malignant neoplasias include hereditary tumors such as, for example, retinoblastoma and Wilms' tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"), while examples of hematological tumors are aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndromes, plasma cell neoplasia, paraneoplastic syndromes, and tumors of unknown primary location as well as AIDS-related malignancies.

A preferred aspect of the present disclosure includes a method for treating breast cancer.

The present invention further relates to the use of the compounds for the manufacture of pharmaceutical compositions, which are used for the treatment, prophylaxis, and/or alleviation of one or more of the aforementioned diseases, preferably for the treatment of one or more of the aforementioned diseases.

This invention further relates to the use of compounds for the production of pharmaceutical compositions for the treatment, prevention or mitigation, preferably for the treatment of hyperproliferative diseases and/or disorders that respond to the induction of apoptosis, such as for example benign or malignant neoplasia, especially malignant neoplasia, and specifically cancer, especially those tumors and types of tumors that have been mentioned just now.

The present invention further relates to the use of compounds according to the present invention for the production of pharmaceutical compositions for the treatment, prevention or mitigation, preferably the treatment of benign or malignant neoplasia, especially malignant neoplasia, and specifically cancer, such as for example any type of tumor disease or tumor types mentioned above.

The present invention additionally relates to a compound according to the present invention or to a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis, and preferably for the treatment of (hyper)proliferative diseases and/or disorders responsive to the induction of apoptosis, which includes benign neoplasia and malignant neoplasia, including cancer.

This invention additionally relates to the use of a compound according to this invention or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical composition for the treatment, prevention or mitigation of a disease that is mediated by a misregulated function of a single protein kinase or multiple protein kinases and/or disorders that contribute to the induction of apoptosis.

The present invention additionally relates to a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis, preferably for the treatment of (hyper)proliferative diseases and/or disorders responsive to the induction of apoptosis, which includes benign neoplasia and malignant neoplasia, including cancer.

The present invention further relates to the use of the compounds and their pharmaceutically acceptable salts according to the present invention for the production of pharmaceutical compositions, which can be used to sensitize to chemotherapeutics and/or anticancer agents that act on target.

The present invention further relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions, which can be used for sensitizing to radiation therapy of the aforementioned diseases, especially cancer.

The present invention further relates to the use of compounds according to the present invention for the manufacture of pharmaceutical compositions which can be used in the treatment of diseases which are sensitive to protein kinase inhibition therapy and which are different from cellular neoplasia. Said non-malignant diseases include, but are not limited to, benign prostatic hyperplasia, neurofibromatosis, various dermatoses, and myelodysplastic syndromes.

Procedures for the treatment of angiogenic disorders

This disclosure also provides methods for the treatment of disorders and diseases associated with increased and/or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be fatal to the organism. Numerous pathological conditions are associated with the growth of foreign blood vessels. Mentioned includes, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD; see, Lopez et al. Invest.

Ophthalmol. Vis. Sci.

1996, 37, 855), neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. The increased blood flow associated with tumor and neoplastic tissue promotes growth, leading to rapid tumor growth and metastasis. The rest of the new blood and lymphatic vessels in the tumor provide an exit route for escaped cells, enhancing metastasis and the subsequent spread of the cancer. The compounds of the present invention can be used for the treatment and/or prevention of any of the angiogenetic disorders mentioned earlier, for example, by inhibiting and/or reducing the formation of blood vessels; by inhibiting, blocking, reducing, decreasing, etc. proliferation of endothelial cells or other types involved in angiogenesis, as well as by causing cell death or apoptosis of said cell types.

The present invention further relates to pharmaceutical compositions comprising one or more compounds according to the present invention and a pharmaceutically acceptable carrier or diluent.

The present invention additionally relates to pharmaceutical compositions comprising one or more compounds according to the present invention and pharmaceutically acceptable excipients and/or excipients.

In the context of the present invention, excipients, carriers, excipients, diluents, carriers or additives mean additives that can be added to said compounds in order to obtain a pharmaceutically acceptable composition suitable for administration.

Thus, the present invention relates to pharmaceutical compositions comprising one or more compounds according to the present invention and one or more pharmaceutically acceptable additives.

Pharmaceutical compositions in accordance with the present invention are prepared by processes known to those skilled in the art. As pharmaceutical compositions, the compounds of the present invention (= active compounds) are used as such, or preferably in combination with suitable pharmaceutical additives, for example in the form of tablets, coated tablets, dragees, pills, cachets, granules, capsules, caplets, suppositories, patches (for example, TTS), emulsions (such as for example micro-emulsions or liquid emulsions), suspensions (such as for example nano-suspensions), gels, solubilizes or solutions (on for example, sterile solutions), or encapsulated in liposomes or in inclusion complexes with beta-cyclodextrin or with beta-cyclodextrin derivatives or the like, where the content of the active compound ranges between 0.1 and 95% whereby, with the help of an appropriate selection of additives, a pharmaceutical form for administration (for example, a form for sustained release or entero-form) is formed that is exactly suitable for the mentioned active compounds and/or for the desired effect.

One skilled in the art is familiar with the excipients, carriers, excipients, diluents, carriers, or additives that are appropriate for the desired pharmaceutical formulations, preparations, or compositions based on his/her expertise. In addition to solvents, gel forming agents, fat bases and other additives added to the active compound, for example antioxidants, dispersants, emulsifying agents, preservatives, solubilizers (such as polyoxyethylene glycerol tricinoleate 35, PEG 400, Tween 80, Captizol, Solutol HS15 and the like), colorants, complexing agents, permeation promoters, stabilizers, fillers, can be used. binders, thickening agents, disintegrating agents, buffers, pH regulators (for example, with the aim of obtaining neutral, alkaline or acidic formulations), polymers, lubricants, capping agents, propellants, tonicity adjusting agents, surfactants, flavoring agents, sweeteners or colors.

Specifically, additives of the type appropriate to the desired formulation and the desired mode of administration may be used.

The administration of said compounds, pharmaceutical compositions or combinations according to the present invention can be carried out by any generally accepted mode of administration known in the art. Illustrative examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous deliveries are preferred.

In general, said pharmaceutical compositions according to the present invention can be administered so that the dose of the active compound is within the range that is common for inhibitors of the Pi3K/Akt pathway. Specifically, a dosage ranging from 0.01 to 4000 mg of active compound per day is preferred in an average adult patient having a body weight of 70 kg. In this regard, it should be noted that the dose is dependent, for example, on the specific compound used, species treated, age, body weight, general health, sex and diet of the treated subject, mode and time of administration, rate of excretion, strength of the disease being treated, and combination of drugs.

The pharmaceutical composition can be administered in a single dose throughout the day or in multiple sub-doses, for example, 2 to 4 doses per day. A single dosage unit of said pharmaceutical composition may contain, for example, from 0.01 mg to 4000 mg, preferably from 0.1 mg to 2000 mg, better from 0.5 to 1500 mg, even better from 1 to 500 mg of active compound. Furthermore, the mentioned pharmaceutical composition can be adapted to a weekly, monthly or even less frequent administration, for example with the help of using an implant, for example a subcutaneous or intramuscular implant, with the help of using an active compound in the form of a poorly soluble salt or with the help of using an active compound that is attached to a polymer.

The present invention additionally relates to a combination comprising one or more first active ingredients selected from the compounds of the present invention and one or more second active ingredients selected from chemotherapeutics (anticancer agents) and anticancer agents that act in a targeted manner, for example for the treatment, prevention or mitigation of diseases that respond to or are sensitive to inhibition of the Pi3K/Akt pathway, such as hyperproliferative diseases that behave benignly or malignantly and/or disorders that are sensitive to the induction of apoptosis, or more specifically, benign or malignant hyperplasia, especially cancer, such as for example any of the previously described tumor diseases, and especially breast cancer.

This invention additionally relates to the use of a pharmaceutical composition comprising one or more compounds according to this invention as the only active ingredient (or more) and some pharmaceutically acceptable carrier or diluent for the production of pharmaceutical products for the treatment and/or prophylaxis of the diseases mentioned here.

This invention additionally relates to the use of a pharmaceutical composition comprising one or more compounds according to this invention as a single active ingredient (or more) and pharmaceutically acceptable additives for the production of pharmaceutical products for the treatment and/or prophylaxis of the diseases mentioned here.

Depending on the particular disease being treated or prevented, additional therapeutically active agents commonly administered for the treatment or prevention of said disease may sometimes be co-administered with the compounds of the present invention. As used herein, additional therapeutic agents commonly administered to treat and prevent a particular disease are known to be appropriate for said disease being treated.

The anti-cancer agents mentioned herein as a combination of compounds according to the present invention should include their pharmaceutically acceptable derivatives, such as for example their pharmaceutically acceptable salts.

One skilled in the art is familiar with the total daily dose(s) and form(s) for administration of said co-administered therapeutic agent(s). Said total daily dose(s) may vary widely depending on the combination agent.

In practicing the present invention, the compounds of the present invention may be administered in combination therapy separately, sequentially, simultaneously, concurrently, or chronologically alternating (such as, for example, combined unit doses, separate unit doses, separate discrete unit doses, fixed or non-fixed combinations, kit of parts or mixtures) with one or more standard therapeutics (chemotherapeutics and/or targeted treatment agents), and in particular anti-tumor agents for targeted therapy, such as any of the ones just mentioned.

In this context, this invention additionally relates to a combination comprising the first active ingredient, which is at least one compound according to the present invention, and some other active ingredient, which is at least one anti-cancer agent known to the state of the art, such as for example one or more of the aforementioned, for separate, consecutive, simultaneous, competitive or chronological alternating use in therapy, such as for example in the therapy of any of the aforementioned diseases.

This invention further relates to a pharmaceutical composition comprising a first active ingredient, which is at least one compound according to the present invention, and a second active ingredient, which is at least one anti-cancer agent known in the art, such as for example one or more of the aforementioned, and, sometimes, some pharmaceutically acceptable carrier or diluent, for successive, consecutive, simultaneous, competitive or chronologically alternating use in therapy.

This invention further relates to a combination product comprising a.) at least one compound according to the present invention which is formulated with some pharmaceutically acceptable carrier or diluent, and b.) at least one anticancer agent known in the art, such as for example one or more of the aforementioned, which is formulated with some pharmaceutically acceptable carrier or diluent.

The present invention further relates to a kit of parts comprising a preparation with a first active ingredient, which is a compound according to the present invention, and a pharmaceutically acceptable carrier or diluent; a preparation with a second active ingredient, which is some known anticancer agent, such as one of those just mentioned, and some pharmaceutically acceptable carrier or diluent; for simultaneous, concurrent, consecutive, separate or chronologically alternating use in therapy. Sometimes, said set of chemicals includes instructions for use during therapy, for example with the aim of treating hyperproliferative diseases and diseases that respond or are sensitive to inhibition of the Pi3K/Akt pathway, such as for example benign or malignant neoplasias, especially cancer, and more precisely any of the already mentioned tumor diseases.

The present invention further relates to a combination preparation comprising at least one compound according to the present invention and at least one anticancer agent known in the art for simultaneous, concurrent, sequential or separate administration.

The present invention further relates to combinations, compositions, formulations, preparations or kits of chemicals according to the present invention that act as inhibitors of the Pi3K/Akt pathway.

In addition, this disclosure further relates to a method for the treatment (with combination therapy) of hyperproliferative diseases and/or disorders that are sensitive to the induction of apoptosis, such as, for example, cancer in a patient, wherein said method comprises administering a combination, composition, formulation, preparation or set of chemicals, as described herein, to said patient in need thereof.

In addition, this disclosure additionally relates to a method for the treatment of hyperproliferative diseases that behave benignly or malignantly and/or disorders that correspond to the induction of apoptosis, such as for example cancer in a patient, wherein said method includes administering, through combined therapy, separately, simultaneously, competitively, sequentially or chronologically alternating, pharmaceutically active and therapeutically effective and tolerable amounts of a pharmaceutical composition, which includes a compound according to the present invention and a pharmaceutically acceptable carrier or a diluent, and a pharmaceutically active and therapeutically effective and tolerable amount of one or more anticancer agents known in the art, such as for example one or more of the aforementioned, to said patient in need thereof.

In addition, this disclosure relates to a method for the treatment, prevention or mitigation of hyperproliferative diseases and/or disorders that are sensitive to the induction of apoptosis, such as for example benign or malignant neoplasia, for example cancer, especially any of the aforementioned tumor diseases, in a patient, wherein said method comprises administering separately, simultaneously, concurrently, sequentially or chronologically alternating to said patient in need, a certain amount of a first active compound, which is a compound according to this invention, and a certain amount of at least one other active compound, at least one other active compound that is a standard therapeutic agent, especially at least one already known anti-cancer agent, such as for example one or more of the already mentioned chemotherapeutics and anti-cancer agents that are known to the state of the art, wherein the mentioned amounts of the first active compound and the mentioned second active compound create a therapeutic effect.

In addition, this disclosure relates to a method for the treatment, prevention or mitigation, especially the treatment of hyperproliferative diseases and/or disorders that respond to induction of apoptosis, such as for example benign or malignant neoplasia, especially malignant neoplasia, for example cancer, especially any of the aforementioned tumor diseases and already mentioned tumor types in a patient, wherein said method includes the administration of combinations in accordance with the present invention.

In addition, this disclosure additionally relates to the use of a composition, combination, formulation, preparation or set of chemicals in accordance with this invention for the production of a pharmaceutical product, such as for example a commercial package or drug, for the treatment, prevention or mitigation, in particular the treatment of hyperproliferative diseases, and/or disorders that respond to the induction of apoptosis, such as for example malignant or benign neoplasia, especially malignant neoplasia, such as for example cancer, especially the already mentioned diseases and types of tumors.

The present invention further relates to a commercial package comprising one or more compounds of the present invention together with instructions for the simultaneous, concurrent, sequential or separate use of one or more chemotherapeutic or anti-cancer agents for targeted treatment, such as for example any of the aforementioned.

The present invention further relates to a commercial package comprising generally one or more compounds of the present invention as a single active ingredient together with instructions for the simultaneous, concurrent, sequential or separate use of one or more chemotherapeutics and/or anti-cancer agents for targeted treatment, such as for example any of the aforementioned.

The present invention further relates to a commercial package comprising one or more chemotherapeutics and/or targeted anticancer agents, such as for example any of those mentioned herein, together with instructions for the simultaneous, concurrent, sequential or separate use of one or more compounds in accordance with the present invention.

Said compositions, combinations, preparations, formulations, kits of chemicals or packages, which are mentioned in the context of combination therapy according to the present invention may also include more than one compound according to the present invention and/or more than one already mentioned antitumor agent known in the state of the art.

Said first and second active ingredient from a combination or set of parts in accordance with the present invention may be provided as separate formulations (ie, independently of each other), which are subsequently mixed for simultaneous, competitive, sequential, separate or chronologically alternating use in combination therapy; or are packaged and presented together as separate components of a combination package for simultaneous, concurrent, sequential, separate, or chronologically alternating use in combination therapy.

The type of pharmaceutical formulation of the first and second active ingredients of a combination or kit of parts according to the present invention may be such that both ingredients are formulated in separate tablets or capsules, or may be different, i.e. suitable for different forms of administration, so that for example one active ingredient is formulated as a tablet or capsule and another is formulated for example for intravenous administration.

The amounts of the first and second active ingredients from the mentioned combinations, compositions or sets of chemicals according to the present invention can together create a therapeutically effective amount for the treatment, prophylaxis or mitigation of hyperproliferative diseases and/or disorders that are sensitive to the induction of apoptosis, especially one of the aforementioned diseases, such as for example malignant or benign neoplasia, and especially malignant neoplasia, for example cancer, such as any type of tumor diseases or tumor types mentioned here.

In addition, the compounds of the present invention may be used in the pre- or post-surgical treatment of cancer.

Furthermore, the compounds of the present invention can be used in combination with radiation therapy.

As is known to those skilled in the art, this invention is not limited to the individual embodiments described herein, but covers all modifications of said embodiments that fall within the scope of this invention as defined by the appended claims.

The following examples illustrate the invention in detail, without limiting it. Additional compounds according to the present invention, the preparation of which is not explicitly described, can be prepared in an analogous manner.

The compounds mentioned in the examples and their salts represent preferred embodiments of the present invention as well as a claim covering all sub-combinations of the residues of the compounds of formula (I) as disclosed by the specific examples.

The term "in accordance with" in the experimental section is used to indicate that said procedure should be used "analogously to".

Experimental part

The following table shows the abbreviations used in this paragraph, in the section with Examples for Intermediaries and in the section with Examples, if they are not already explained in the text itself. The shapes of the NMR signals (peaks) are listed as they appear in the spectrum, while possible higher-order effects are not considered. Chemical labels were generated using the ACD/Name Batch program, version 12.01, or the AutoNom2000 program implemented in MDL ISIS Draw. In some cases, commonly accepted names for commercially available reagents were used instead of their labels generated with AutoNom2000.

Other abbreviations have their usual meanings known to those skilled in the art. The various aspects of the present invention, which are described in this application, are illustrated by the following examples which do not limit the invention in any way.

Examples

UPLC-MS standard procedures

Analytical UPLC-MS was performed using UPLC-MS Procedure 1 unless otherwise noted. Masses (m/z) are taken from positive electrospray ionization mode unless negative mode (ES-) is specified.

Procedure 1:

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60° C; injection: 2 ul; DAD scan: 210-400 nm; ELSD.

Procedure 2:

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1 mm; eluent A: water + 0.2% ammonia, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60° C; injection: 2 ul; DAD scan: 210-400 nm; ELSD.

Procedure 3:

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1 mm; eluent A: water + 0.1% ammonia, eluent b: acetonitrile; gradient 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60° C; injection: 2Ml; DAD scan: 210-400 nm; ELSD.

Procedure 4:

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1 mm; eluent A: water + 0.2% ammonia, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60° C; injection: 2Ml; DAD scan: 210-400 nm; ELSD.

Examples for Intermediaries

Example for Intermediate lnt-1:

tert-butyl {1 -[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate

Step 1: tert-butyl [1-(4-bromophenyl)cyclobutyl]carbamate

The free base of commercially available 1-(4-bromophenyl)cyclobutanamine hydrochloride [CAS 1193389-40-0] (8.99 g, 34.24 mmol, 1.0 eq.) was prepared as follows: the hydrochloride salt (8.99 g, 34.24 mmol, 1.0 eq.) was dissolved in DCM and washed sequentially with aqueous sodium bicarbonate and water, and the organic part is tested and concentrated.

The crude amine was dissolved in dry THF (120 mL) and diisopropylethylamine (17.62 mL, 102.7 mmol, 3.0 eq.) under a nitrogen atmosphere, and then a solution of di-tert-butylcarbonate (8.22 g, 37.6 mmol, 1.1 eq.) in THF (20 mL) was added. The reaction was mixed on st during the night. The mixture was partitioned between EtOAc and water, and the extracted organic phase was washed with brine and concentrated in vacuo to give the title compound.

Alternatively, said title compound can be prepared using known procedures, such as those described in WVO2008/70041, and in particular from commercially available (4-bromophenyl)acetonitrile.

Step 2: tert-butyl [1-(4-cyanophenyl)cyclobutyl]carbamate

The title compound can be prepared using known procedures, such as those described in document VVO2008/70041, and in particular from tert-butyl [1-(4-bromophenyl)cyclobutyl]carbamate.

Alternatively, tert-butyl [1-(4-cyanophenyl)cyclobutyl]carbamate (CAS 1032349-97-5) can be obtained commercially.

Step 3: tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate

The title compound can be prepared using known procedures, such as those described in document VVO2008/70041, and in particular from tert-butyl [1-(4-cyanophenyl)cyclobutyl]carbamate.

Step 4: tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [InMA]

A mixture of tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (5.0 g, 13.68 mmol, 1.0 eq.) and pyridinium hydrobromide perbromide (4.38 g, 13.68 mmol, 1.0 eq.) in THF (78 mL) was stirred at 0 °C for 30 min. Said mixture was partitioned between EtOAc and water, and the organic phase was washed with aqueous sodium thiosulfate and brine, dried, filtered through silicone-coated filter paper, and concentrated in vacuo to afford the crude title compound (5.44 g, 93% purity by UPLC-MS) which was used without further purification. UPLC-MS (Procedure 4): RT = 1.49 min; m/z = 442.21 (ES-, M-H, M = C23H26<79>BrNO3).

Step 5: tert-butyl {1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate [lnt-1]

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A (1.00 g, -80% purity, 1.87 mmol, 1.0 eq.), 6-methylpyridazin-3-amine (CAS-No. 18591-82-7, 0.245 g, 2.24 mmol, 1.2 equiv.), N,N-diisopropylethylamine (0.33 mL, 1.87 mmol, 1.0 equiv.) and activated 3A molecular sieves in isopropanol (5.7 mL) was heated for 7 h under reflux. After cooling, the mixture was partitioned between DCM and water, mixed vigorously and filtered through a silicon-coated filter paper. The filtrate was concentrated in vacuo.UPLC analysis of the crude product showed >90% purity. The mentioned crude product was used in the next step without additional purification.

UPLC-MS (Procedure 1): RT = 1.41 min; m/z = 455.89 (M+H).

Example for Intermediate lnt-2: tert-butyl {1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)-carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A (1.85 g, -80% purity, 3.45 mmol, 1.0 eq.), 6-ethylpyridazine-3-ammonium chloride (CAS-No. 1178585-42-6, 0.660 g, 4.14 mmol, 1.2 eq.), N,N-diisopropylethylamine (1.20 mL, 6.89 mmol, 2.0 eq.) and activated 3A molecular sieves in isopropanol (1 0.5 mL) was heated for 12 h under reflux. After cooling, the mixture was partitioned between DCM and water, mixed vigorously and filtered through a silicon-coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 100 g charge SNAP: hexane -

>hexane/ethyl acetate, 2/1) to give 700 mg (43% yield) of the title compound in 69% purity (UPLC).

UPLC-MS (Procedure 3): RT = 1.53 min; m/z = 469.34 (M+H).

Example for Intermediate lnt-3:

tert-butyl (1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A (1.85 g, -80% purity, 3.45 mmol, 1.0 eq.), 6-(trifluoromethyl)pyridazin-3-amine (CAS-No. 935777-24-5, 0.674 g, 4.14 mmol, 1.2 eq.), N,N-diisopropylethylamine (0.60 mL, 6.89 mmol, 1.0 eq.) and activated 3A molecular sieves in isopropanol (10.5 mL) was heated for 7 h under reflux. After cooling, the mixture was partitioned between DCM and water, mixed vigorously and filtered through a silicon-coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 100 g charge SNAP: hexane -

>hexane/ethyl acetate, 2/1) to give 680 mg (34% yield) of the title compound. UPLC-MS (Procedure 3): RT = 1.56 min; m/z = 509.29 (M+H).

Example for Intermediate lnt-4:

Ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate, which was obtained in a manner analogous to that described in Example Intermediate Int-1-A (3.3 g, -80% purity, 5.79 mmol), ethyl 6-aminopyridazine-3-carboxylate (CAS-No. 98548-01-7, 1 g, 5.57 mmol), of N,N-diisopropylethylamine (0.97 mL, 5.57 mmol) and activated 3A molecular sieves in isopropanol (30.4 mL) was heated for 20 h under reflux. After cooling, the mixture was partitioned between DCM and water, mixed vigorously and filtered through a silicon-coated filter paper. The filtrate was concentrated in vacuo, dissolved in DCM and washed with dilute aqueous hydrochloric acid (1N) and brine, dried and concentrated in vacuo to give the crude title compound. Purification was accomplished by silica chromatography (gradient elution: Hexane:EtOAc, 9:1 to Hexane:EtOAc, 1:1) to give the title compound (2.80 g, 92% purity, 90% yield). UPLC-MS (Procedure 3): RT = 1.51 min; m/z = 513.41 (M+H).

1H-NMR (400 MHz, d6-DMSO): δ = 8.29 (d, 1H), 7.74 (d, 1H), 7.50-7.56 (m, 8H), 7.31 (d, 2H), 4.33 (q, 2H), 2.28-2.39 (m, 4H), 1.88-1.99 (m, 1H), 1.68-1.80 (m, 1H), 1.26-1.29 (m, 9H), 1.08 (br s, 3H).

Example for Intermediate lnt-5:

tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A (0.67 g, 1.50 mmol), 3-amino-6-methoxypyridazine (CAS Reg. No. 7252-84-8, 0.23 g, 1.80 mmol, 1.2 eq.), N,N-diisopropylethylamine (0.74 mL, 1.50 mmol, 1.0 eq.) and activated 3A molecular sieve powder (10 g) in isopropanol (78 mL) was heated at reflux for 8 h. After cooling, the mixture was filtered through a pad of Celite. Said Celite was washed with DCM, and the combined organics were washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.55 g, 78% yield).

UPLC-MS (Procedure 3): RT = 1.52 min; m/z (rel. intensity) 471 (95, (M+H)<+>), 943 (100, 2M+H)<+>); ES- m/z (rel. intensity) 469 (20, (M-H)-).

1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.37 (br s, 6H), 1.65-1.81 br s, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 H, 1H).

Example for intermediate lnt-6:

tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A (5.80 g, 13.1 mmol), 3-amino-4,6-dibromopyridazine (CAS Reg. No. 1206487-35-5, 3.96 g, 15.7 mmol, 1.2 equiv.), N,N-diisopropylethylamine (2.3 mL, 13.0 mmol, 1.0 equiv.) and powdered activated 3A molecular sieves (10 g) in isopropanol (70 mL) was heated at reflux temperature for 8 h. After cooling, the mixture was filtered through a pad of Celite. Said Celite was washed with DCM and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure. The remaining material was purified by MPLC (Biotage Isolera; 100 g feed SNAP: 100% hexane 2.0 min, gradient to 75% hexane / 25% EtOAc 2.5 min, 75% hexane / 25% EtOAc 4.5 min, gradient to 50% hexane / 50% EtOAc 2 min, 50% hexane / 50% EtOAc 4.5 min, gradient to 100% EtOAc 2.5 min, 100% EtOAc 5.7 min) to give partially purified tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (2.65 g,

-82% purity, 28% yield):

UPLC-MS (Procedure 3): RT = 1.67 min; m/z (rel. intensity) 597 (50, (M+H)+). 1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.37 (br s, 6H), 1.65-1.81 (m, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 Hz, 1H).

The following examples were prepared in a manner analogous to Example for Intermediate lnt-6 by reacting the appropriate amine with tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [prepared in a manner analogous to that described in Example for Intermediate lnt-1 A]

Example for Intermediate lnt-7:

tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A solution of tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6 (0.10 g, 0.17 mmol in MeOH (3 mL)) was cooled in an ice bath and treated dropwise with sodium methoxide. (0.5 M in MeOH, 0.40 ml, 0.20 mmol, 1.2 equiv.) The resulting solution was allowed to warm to room temperature and was stirred at room temperature, after which more sodium methoxide was added (0.40 ml, 0.20 mmol, 1.2 equiv.). temperature for 2 h, after which more sodium was added of methoxide (0.5 M in MeOH, 0.40 ml, 0.20 mmol, 1.2 eq.). The resulting solution was added to ice water, and the aqueous mixture was extracted with DCM (3 x 25 mL). The combined organic phases were dried (Na2SO4 anhydrous) and concentrated under reduced pressure to give crude tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (102 mg, -78% purity). This material was used without further purification: UPLC-MS (Procedure 3): RT = 1.67 min; m/z (rel. intensity) 549 (90, (M+H)<+>). 1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.37 (br s, 6H), 1.65-1.81 (br s, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 (m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 H, 1H).

The following examples were prepared in a manner analogous to that of Example for Intermediate lnt-7 by reacting the appropriate carbamate with sodium methoxide in methanol.

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-7 by reacting the appropriate carbamate with sodium ethoxide in ethanol.

Example for Intermediate lnt-8:

tert-butyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A solution of tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6 (0.66 g, 1.10 mmol), in MeOH (10 mL) was treated dropwise with sodium methoxide (0.5 M in MeOH, 11.0 mL, 5.51 mmol, 5.0 equiv.), and the resulting mixture was stirred at room temperature for 12 h. The resulting solution was irradiated at 120°C in a microwave oven for 90 min. The resulting solution was added to ice water, and the aqueous mixture was extracted with DCM (3 x 50 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g feed SNAP: 100% hexane 2.0 min, gradient to 70% hexane / 30% DCM 3 min, 70% hexane / 30% DCM 3 min, gradient to 50% hexane / 50% DCM 4 min, 50% hexane / 50% DCM 3.5 min, gradient to 95% hexane / 5% DCM 5.5 min, 95% hexane / 5% DCM 5.5 min) to give tert-butyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.19 g, 34%) followed by methyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.029 g, 5.4%). tert-butyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}-cyclobutyl)carbamate: UPLC-MS (Procedure 3): RT = 1.53 min; m/z (rel. intensity) 501 (50, (M+H)<+>). 1H-NMR (d6-DMSO): δ 1.00-1.18 (br s, 3H), 1.22-1.35 (br s, 6H), 1.67-1.79 (br s, 1H), 1.87-1.98 (br s, 1H), 2.27-2.37 (m, 4H), 3.77 (s, 3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.48 (m, 5H), 7.52-7.56 (m, 2H).

Methyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}-cyclobutyl)carbam UPLC-MS (Procedure 3): RT = 1.36 min; m/z (rel. intensity) 459 (70, (M+H)<+>); ES-m/z (rel. intensity) 457 (10, (M-H)).

1H-NMR (d6-DMSO): δ 1.66-1.81 (m, 1H), 1.86-2.02 (br s, 1H), 2.35 (br t, J=7.3 Hz, 4H), 3.41 (br s, 3H), 3.76 (s, 3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.51 (m, 5H), 7.51-7.57 (m, 2H), 7.87 (br s, 1H).

Example for Intermediate lnt-9:

Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

To a solution of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-7 (0.41 g, 0.75 mmol), in MeOH (10 mL) and THF (1 mL) were added in an autoclave. 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride (0.12 g, 0.15 mmol, 0.20 eq.) and triethylamine (0.11 ml, 0.82 mmol, 1.1 eq.). The autoclave was flushed with CO (approximately 5 bar) three times, then the pressure was increased with the help of CO (5.2 bar), and everything was mixed at room temperature for 30 min, while everything was briefly left under a pressure of one atmosphere (0.06 bar). The autoclave was then pressurized again with CO (5.9 bar at 20° C), heated to 110° C, and everything was mixed at the same temperature for 22 h. The resulting solution was concentrated under reduced pressure. The resulting material was crystallized from MeOH to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.34 g, 85%): UPLC-MS (Procedure 3): RT = 1.46 min; m/z (rel. intensity) 529 (70, (M+H)<+>); ES-m/z (rel. intensity) 527 (5, (M-H)-).

1H-NMR (d6-DMS0): δ 1.00-1.18 (br s, 3H), 1.22-1.35 (br s, 6H), 1.67-1.79 (br s, 1H), 1.87-1.98 (br s, 1H), 2.27-2.37 (m, 4H), 3.77 (s, 3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.48 (m, 5H), 7.52-7.56 (m, 2H).

Example for Intermediate lnt-10: tert-butyl {1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-2-

yl)phenyl]cyclobutyl}carbamate (Approach 1)

A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate, which was prepared in a manner analogous to that of Example for Intermediate lnt-9 (0.20 g, 0.38 mmol), in a solution of ammonia in MeOH (7N, 15 mL) and THF (1 mL) was irradiated in microwave at 130° C for 90 min. The solids were collected by filtration to give tert-butyl {1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 63%): UPLC-MS (Procedure 3): RT = 1.30 min; m/z (rel. intensity) 514 (70, (M+H)<+>); ES-m/z (rel. intensity) 512 (90, (M-H)").

1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.39 (br s, 6H), 1.65-1.81 (br s, 1H), 1.86-2.02 (br m, 1H), 2.28-2.39 (m, 4H), 3.77 (s, 3H), 4.13 (s, 3H), 7.15 (s, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.41-7.55 (m, 7H), 7.56-7.62 (m, 2H), 7.82 (br s, 1H).

The following examples were prepared in a manner analogous to that of Example for Intermediate lnt-10 by reacting the appropriate carbamate with a solution of ammonia in MeOH:

The following examples were prepared in a manner analogous to that of Example for Intermediate lnt-10 by reacting the appropriate carbamate with a solution of methylamine in MeOH:

Example for intermediate lnt-11:

tert-butyl {1-[4-{8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

To a mixture of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-7 (0.075 g, 0.14 mmol), and 5% palladium on carbon (0.007 g) in DMF (1 mL) a solution of sodium formate (0.074 g, 1.09 mmol, 8.0 eq.) in water (0.2 mL) was added. The resulting mixture was stirred at 80° C. for 3 h, diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The resulting solution was filtered through a membrane filter, and the solids were washed with MeOH (1 mL). The resulting solution was diluted with EtOAc (25 mL), washed with water (2 x 25 mL), dried (Na2SO4 anhydrous) and concentrated under reduced pressure to give tert-butyl {1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate in approximately 75% purity (0.058 g, 90%): UPLC-MS (Procedure 3): RT = 1.44 min; m/z (rel. intensity) 471 (100, (M+H)<+>); ES-m/z (rel. intensity) 512 (90, (M-H)").

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-11 by reacting the appropriate carbamate with sodium formate and a palladium catalyst.

Example for Intermediate lnt-12:

tert-butyl {1 -[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

A mixture of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-7 (0.30 g, 0.54 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol, 10 mol%) in 1,2-dimethoxyethane (4 mL) was stirred under argon for 10 min, then treated sequentially with K2CO3 (0.075 g, 0.54 mmol, 1.0 equiv.), water (1.5 mL), and vinylboronic anhydride-pyridine complex (prepared as described in J. Org. Chem. 2002, 67, 4968; 0.13 g, 0.54 mmol, 1.0 eq). The resulting mixture was heated at reflux temperature for 16 h, and then added to water (15 mL). The resulting mixture was extracted with EtOAc (2x25 mL). The combined organic phases were washed with water (25 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; loading of 10 g SNAP, 100% hexane 1.5 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 2.0 min, gradient to 50% hexane / 50% EtOAc 3.0 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give tert-butyl {1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.25 g, 92%): UPLC-MS (Procedure 3): RT = 1.55 min; m/z (rel. intensity) 497 (100, (M+H)<+>); ES-m/z (rel. intensity) 495 (10, (M-H)-).

1H-NMR (d6-DMSO): δ 0.80-1.37 (br m, 9H), 1.65-1.80 (br s, 1H), 1.85-2.01 (br m, 1H), 2.27-2.37 (m, 4H), 4.02 (s, 3H), 5.63 (d, J=11.3 Hz, 1H), 6.27 (d, J=17.7 Hz, 1H), 6.64 (dd, J=10.0, 17.7 Hz, 1H), 7.04 (s, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.42-7.55 (m, 8H).

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-12 by reacting the appropriate carbamate with a complex of vinylboronic anhydride and pyridine.

Example for Intermediate lnt-13:

tert-butyl {1-[4-(6-ethyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

A solution of tert-butyl {1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-12 (0.20 g, 0.40 mmol), in methanol (8 ml) was hydrogenated using an H-Cube flow reactor (Pd/C cartridge). The resulting solution was concentrated under reduced pressure to give tert-butyl {1-[4-(6-ethyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.20 g, 100%): 1 H-NMR (d6-DMSO): 5 1.08-1.35 (br m, 9H), 1.19 (t, J=7.5 Hz, 3H), 1.66-1.83 (br s, 1H), 1.85-2.03 (br m, 1H), 2.26-2.37 (m, 4H), 2.68 (q, J=7.5 Hz, 2H), 4.05 (s, 3H), 6.70 (s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.41-7.53 (m, 8H).

The following examples were prepared in a manner analogous to that of Example for Intermediate lnt-13 by hydrogenating the corresponding carbamate using an H-Cube flow reactor.

Example for Intermediate lnt-14:

tert-butyl (1-{4-[6-chloro-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate

A mixture of tert-butyl {1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-7.1 (0.15 g, 0.27 mmol), 3-pyridineboronic acid (0.040 g, 0.33 mmol, 1.2 eq.), 1,1'-bi(diphenylphosphino)ferrocenepalladium(li) dichloride (0.022 g, 0.03 mmol, 0.1 eq.), Na2CO3 (0.086 g, 0.81 mmol, 3.0 eq.), in dioxane (2.9 ml) and water (0.4 ml) was treated with Ar, and then it was left under an argon atmosphere and irradiated in a microwave oven 105° C for 90 min. The reaction mixture was then added to a mixture of water (10 ml), saturated aqueous NH 4 Cl (10 ml) and CH 2 Cl 2 (20 ml). The resulting mixture was vigorously stirred for 30 min. The organic phase was separated, dried (Na2SO4 free), and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g feed SNAP, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 2.5 min, 50% hexane / 50% EtOAc 3.5 min, gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give tert-butyl (1-{4-[6-chloro-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.046 g, 31%): UPLC-MS (Procedure 3): RT = 1.62 min; m/z (rel. intensity) 552 (100, (M+H)<+>); ES-m/z (rel. intensity) 550 (10, (M-H) ).

1H-NMR (d6-DMSO): δ 0.98-1.37 (br m, 9H), 1.66-1.81 (br s, 1H), 1.85-2.00 (br m, 1H), 2.27-2.38 (m, 4H), 7.31 (d, J=8.5 Hz, 2H), 7.49-7.58 (m, 7H), 7.64 (ddd, J=7.0, 4.7, 0.8 Hz, 1H), 7.85 (s, 1H), 8.75 (ddd, J=4.9, 1.5 Hz, 1H), 8.81 (possible dt, J=8.1, 1.9 Hz, 1H), 9.56 (dd, J= 2.3, 0.6 Hz, 1H).

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-14 by reacting the appropriate carbamate with [1-(tert-butoxycarbonyl)-! H-pyrazol-4-yl]boronic acid.

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-14 by reacting the appropriate carbamate with [1-(tert-butoxycarbonyl)-1H-pyrazol-5-yl]boronic acid.

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-14 by reacting the appropriate carbamate with (1-methyl-1H-pyrazol-5-yl)boronic acid.

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-14 by reacting the appropriate carbamate with (4-fluorophenyl)boronic acid.

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-14 by reacting the appropriate carbamate with cyclopropylboronic acid.

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-14 by reacting the appropriate carbamate with pyridine-4-ylboronic acid.

Example for Intermediate lnt-15:

2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazin-8-yl trifluoromethanesulfonate

To a solution of tert-butyl {1-[4-(8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-11.3 (0.34 g, 0.75 mmol), and triethylamine (0.25 mL, 1.73 mmol, 2.3 eq.) in DCM (3 ml) at -20° C. under argon was added dropwise trifluoromethanesulfonic anhydride (0.15 ml, 0.90 mmol, 1.2 eq.). The reaction mixture was allowed to slowly warm to room temperature, then stirred for 1 h, and finally cooled to -10° C. More triethylamine (0.25 mL, 1.73 mmol, 2.3 equiv.) and trifluoromethanesulfonic anhydride (0.15 mL, 0.90 mmol, 1.2 equiv.) were added. The mixture was allowed to warm to room temperature and was stirred for 3 h. The mixture was treated with a mixture of 50% water / 50% saturated solution of NaHCCb (10 mL). The aqueous mixture was extracted with DCM (3x10 mL), dried (Na 2 SO 4 anhydrous), and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g SNAP loading, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 3.5 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 3.5 min, 100% EtOAc 4.5 min) to give 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl

Trifluoromethanesulfonate (0.15 mg, 34%):

UPLC-MS (Procedure 3): RT = 1.63 min; m/z (rel. intensity) 588 (40, (M+H)<+>); ES-m/z (rel. intensity) 587 (20, (M-H)").

1H-NMR (d6-DMSO): 6 1.00-1.36 (br m, 9H), 1.68-1.80 (br s, 1H), 1.88-2.00 (br m, 1H), 2.30-2.38 (m, 4H), 7.33 (d, J=8.6 Hz, 2H), 7.47-7.57 (m, 7H), 7.62, (d, J=5.3 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H).

Example for Intermediate lnt-16:

tert-butyl {1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

To a solution of tert-butyl {1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate int-6.1 (2.49 g, 4.50 mmol), in DMF (63 mL) was added potassium acetate (2.21 g, 22.5 mmol, 5.0 equiv.), and the resulting mixture was irradiated in a microwave at 140° C for 90 min. The resulting mixture was added to ice water (200 ml). Said aqueous mixture was extracted with a mixture of DCM/isopropanol solution, 4:1, (4 x 50 ml). The combined organic phases were dried (Na 2 SO 4 anhydrous), and concentrated under reduced pressure to give a brown oil (2.6 g). Said oil was triturated with MeOH to give tert-butyl {1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate as a yellow powder (0.60 g, 27%): UPLC-MS (Procedure 3): RT = 0.93 min; m/z (rel. intensity) 491 (100, (M+H)<+>), 981 (80 (2M+H)<+>); ES- m/z (rel. intensity) 489 (100, (M-H)-).

1H-NMR (d6-DMSO): 6 1.00-1.35 (br m, 9H), 1.65-1.80 (br s, 1H), 1.86-1.99 (br m, 1H), 2.25-2.39 (m, 5H), 6.45 (s, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.42-7.52 (m, 8H).

Example for Intermediate lnt-17:

tert-butyl (1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate

To a solution of tert-butyl {1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-16 (1.90 g, 3.87 mmol), in DMF (50 mL) was added cesium carbonate (6.88 g, 11.6 mmol, 3.0 equiv.) and benzyl bromide (0.58 ml, 4.84 mmol, 1.25 equiv.), and the resulting mixture was irradiated in a microwave oven at 140°C for 90 min. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was added to ice water (100 ml). The aqueous mixture was extracted with a mixture of DCM/isopropanol solution, 4:1, (3 x 50 ml). The combined organic phases were dried (Na 2 SO 4 anhydrous), and concentrated under reduced pressure. The resulting oil was triturated with ethanol to give tert-butyl (1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate as a powder (0.93 g, 41%): UPLC-MS (Procedure 3): RT = 1.51 min; m/z (rel. intensity) 581 (100, (M+H)<+>); ES-m/z (rel. intensity) 579 (90, (M-H)").

1H-NMR (d6-DMSO): δ 0.98-1.35 (br m, 9H), 1.64-1.78 (br s, 1H), 1.84-2.00 (br m, 1H), 2.25-2.37 (m, 4H), 5.48 (s, 2H), 7.08 (s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.37-7.57 (m, 13H).

Example for Intermediate lnt-18: Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-

phenylimidazo[1,2-b]pyridazine-6-carboxylate

To a solution of tert-butyl (1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-17 (0.91 g, 1.48 mmol), in MeOH (20 mL) and THF (2 mL) were added in an autoclave. 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride (0.24 g, 0.30 mmol, 0.20 eq.) and triethylamine (0.23 ml, 1.63 mmol, 1.1 eq.). The autoclave was flushed with CO (approximately 5 bar) three times, and then the pressure was increased with the help of CO (5.2 bar), everything was mixed at room temperature for 30 min and then briefly left under lower pressure conditions (0.06 bar). The pressure in the autoclave was then increased again with the help of CO (5.9 bar at 20° C), everything was heated to 100° C, and it was mixed at the same temperature for 18 h. The resulting solution was concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 25 g SNAP feed, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 6.0 min, 50% hexane / 50% EtOAc 6.5 min, gradient to 10% hexane / 90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 26.7 min) which gives methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.34 g, 44%): UPLC-MS (Procedure 3): RT = 0.89 min; m/z (rel. intensity) 515 (100, (M+H)<+>); ES-m/z (rel. intensity) 513 (100, (M-H)").

Example for intermediate lnt-19:

Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-ethoxy-3-

phenylimidazo[1,2-b]pyridazine-6-carboxylate

A mixture of methyl 2-(4-{1 -[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate, which was prepared in a manner analogous to that described in Example Intermediate lnt-18 (0.16 g, 0.32 mmol), ethyl iodide (0.50 mL, 0.63 mmol, 2.0 eq.) and cesium carbonate (0.31 g, 0.94 mmol, 3.0 eq.) in DMF (6 mL) was stirred for 1 h at room temperature and then at 50° C. for 3 h. The reaction mixture was then added to ice water (20 mL). The aqueous mixture was extracted with a mixture of DCM/isopropanol solution, 4:1, (2 x 25 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g SNAP feed, 80% hexane / 20% EtOAc 3.0 min, gradient to 55% hexane / 45% EtOAc 2.0 min, 55% / 45% EtOAc 3.0 min, gradient to 4% hexane / 96% EtOAc 5.5 min, gradient to 100% EtOAc 0.5 min, 100% EtOAc 7.2 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.072 g, 42%): UPLC-MS (Procedure 3): RT = 1.50 min; m/z (rel. intensity) 543 (100, (M+H)<+>); ES-m/z (rel. intensity) 541 (10, (M-H)-).

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-19 by reacting the appropriate phenol with 2-methoxyethyl bromide.

Example for Intermediate lnt-20: tert-butyl (1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]-pyridazine-2-

yl]phenyl}cyclobutyl)carbamate

A mixture of tert-butyl {1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-7.1 (0.78 g, 1.42 mmol), 1H-imidazol-2-ylboronic acid (0.024 g, 2.13 mmol, 1.5 eq.), 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride, CDM complex, (0.12 g, 0.14 mmol, 0.1 eq.) and cesium fluoride (0.65 g, 4.25 mmol, 3.0 eq.) in dimethoxymethane (12 mL) was treated with Ar, and then left under an argon atmosphere. a clogged container, so it was heated on 100° C for 3 days. The reaction mixture was then added to ice water (50 mL). The aqueous mixture was extracted with a mixture of DCM/isopropanol solution, 4:1, (4 x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The resulting material was purified with the help of MPLC (Biotage Isolera; charge of 25 g

SNAP, 100% hexane 2.0 min, gradient to 50% hexane / 20% EtOAc 3.5 min, 50% hexane / 50% EtOAc 4.5 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 8.7 min) which gives tert-butyl (1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.28 g, 37%): UPLC-MS (Procedure 3): RT = 1.54 min; m/z (rel. intensity) 541 (100, (M+H)<+>); ES-m/z (rel. intensity) 539 (30, (M-H) ).

1H-NMR (d6-DMSO): δ 1.00-1.37 (br m, 9H), 1.68-1.80 (br s, 1H), 1.88-2.00 (br m, 1H), 2.27-2.39 (m, 4H), 7.27 (possible q, J=0.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.50-7.55 (m, 5H), 7.59 (d, J=8.6 Hz, 2H), 7.92 (s, 1H), 8.81 (possible t, J=1.4 Hz, 1H), 9.28-9.29 (m, 1H).

Example for Intermediate lnt-21:

tert-butyl {1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-2-

yl)phenyl]cyclobutyl}carbamate (Approach 2)

To a solution of tert-butyl {1-[4-(6-chloro-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-7.3 (0.54 g, 1.00 mmol), in a solution of ammonia in MeOH (7N; 5.7 mL, 40 mmol, 40 eq.) 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride, DCM complex, (0.16 g, 0.20 mmol, 0.20 eq.) was added to the autoclave. The autoclave was washed with CO (approximately 5 bar) three times, and then the pressure was increased with the help of CO (5.2 bar), everything was mixed at room temperature for 30 min, then it was briefly left under lower pressure conditions (0.06 bar). The pressure in the autoclave was then increased with the help of CO (5.9 bar at 20° C), everything was heated to 100° C, and it was mixed at the same temperature for 18 h. The resulting material was filtered and concentrated under reduced pressure to give tert-butyl {1 -[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.29 g, 57%): UPLC-MS (Procedure 3): RT = 1.29 min; m/z (rel. intensity) 514 (70, (M+H)<+>); ES-m/z (rel. intensity) 512 (100, (M-H)-).

Example for Intermediate lnt-22:

Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-8-carboxylate

To a solution of 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl trifluoromethanesulfonate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-15 (0.15 g, 0.25 mmol), in MeOH (0.4 ml) and THF (0.04 ml) were added in an autoclave. 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride (0.040 g, 0.050 mmol, 0.20 eq.) and triethylamine (0.040 ml, 0.27 mmol, 1.1 eq.). The autoclave was washed with CO (approximately 5 bar) three times, and then the pressure was increased with the help of CO (5.2 bar), everything was mixed at room temperature for 30 min, then it was briefly left under conditions of lower pressure (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20°C), heated to 100°C, and everything was mixed at the same temperature for 18 hours. The resulting solution was concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g SNAP loading, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 2.5 min, gradient to 70% hexane / 30% EtOAc 3.0 min, 70% hexane / 30% EtOAc 2.5 min, gradient to 50% hexane / 50% EtOAc 3.5 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 1.0 min, 100% EtOAc 5.8 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate (0.081 g, 63%): UPLC-MS (Procedure 3): RT = 1.46 min; m/z (rel. intensity) 499 (100, (M+H)<+>), 997 (70, (2M+H)<+>); ES- m/z (rel. intensity) 497 (20, (M-H)").

1H-NMR (d6-DMSO): δ 1.00-1.36 (br m, 9H), 1.65-1.81 (br s, 1H), 1.86-2.02 (br m, 1H), 2.26-2.38 (m, 4H), 3.98 (s, 3H), 7.31 (d, J=8.5 Hz, 2H), 7.46-7.58 (m, 8H), 7.64 (d, J=4.5 Hz, 1H), 8.58 (d, J=4.7 Hz, 1H).

Example for Intermediate lnt-23:

Dimethyl 2-(4-{1 -[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-6,8-dicarboxylate

To a solution of tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6 (0.51 g, 0.80 mmol), in MeOH (1.3 mL) and THF (0.13 mL) were added in an autoclave. 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride (0.13 g, 0.16 mmol, 0.20 equiv.) and triethylamine (0.12 mL, 0.88 mmol, 1.1 equiv.). The autoclave was washed with CO (approximately 5 bar) three times, and then the pressure was increased with the help of CO (5.2 bar), everything was mixed at room temperature for 30 min, then it was briefly left under conditions of reduced pressure (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20°C), heated to 100°C, and everything was mixed at the same temperature for 18 hours. The resulting solution was concentrated under reduced pressure. The material was then filtered and concentrated under reduced pressure to give dimethyl 2-(4-{1-[(tetra-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxylate (0.45 g, 100%), which was used without further purification: UPLC-MS (Procedure 3): RT = 1.46 min; m/z (rel. intensity) 557 (100, (M+H)<+>).

Example for Intermediate lnt-24: tert-butyl {1-[4-(6,8-dicarbamoyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate (1) and 2-[4-(1-minocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide (2, Accession 1)

A solution of dimethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxylate, which was prepared in a manner analogous to that described in Example Intermediate lnt-23 (0.45 g, 0.81 mmol), in ammonia solution in MeOH (7N, 11.5 mL) was irradiated. in a microwave oven at 130° C for 90 min. The resulting mixture was concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isoler; 25 g SNAP loading, 100% DCM 4.5 min, gradient to 95% DCM / 5% MeOH 1.0 min, 95% DCM / 5% MeOH 5.0 min, gradient to 90% DCM / 10% MeOH 1.0 min, 90% DCM / 10% MeOH 8.1 min, gradient to 80% DCM / 20% MeOH 2.0 min, 80% DCM / 20% MeOH 8.2 min) to give tert-butyl {1-[4-(6,8-dicarbamoyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.34 g, 8%), and then 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide (0.63 g, 18%).

tert-butyl {1 -[4-(6,8-dicarbamoyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (1): UPLC-MS (Procedure 3): RT = 1.28 min; m/z (rel. intensity) 527 (100, (M+H)<+>); ES-m/z (rel. intensity) 525 (60, (M-H)-).

2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide

UPLC-MS (Procedure 3): RT= 1.02 min; m/z (rel. intensity) 410 (100 (M+H-17)<+>), 427 (70, (M+H)<+>), 853 (20, (2M+H)<+>); ES- m/z (rel. intensity) 425 (100, (M-H)"), 851 (10, (M-H)-).

Example for Intermediate lnt-25:

tert-butyl {1-[4-(6-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

To a solution of tert-butyl {1-[4-(6-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6.3 (0.10 g, 0.22 mmol), in DCM (4 mL) was added pyridine (0.036 mL, 0.44 mmol, 2 eq.) and acetic anhydride (0.027 mL, 0.29 mmol, 1.3 eq.). The reaction mixture was stirred for 24 h at room temperature, then an additional amount of acetic anhydride (0.042 mL, 0.44 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for an additional 24 h. The resulting mixture was concentrated under reduced pressure to give tert-butyl {1-[4-(6-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.11 g, 100%) which was used without further purification: UPLC-MS (Procedure 3): RT = 1.34 min; m/z (rel. intensity) 498 (100, (M+H)<+>), 995 (60, (M+H)<+>); ES- m/z (rel. intensity) 496 (50, (M-H)"), 993 (10, (2M-H)").

The following examples were prepared in a manner analogous to that of Example Intermediate lnt-25 by reacting tert-butyl {1-[4-(6-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (Example Intermediate lnt-6.3) or tert-butyl {1-[4-(8-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (Example for Intermediate lnt-6.6) with the corresponding anhydride.

Example for Intermediate lnt-26:

tert-butyl (1-{4-[6-(methylsulfonyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

To a solution of tert-butyl (1-{4-[6-(methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6.4 (0.10 g, 0.21 mmol), in chloroform (4 ml) was added meta-chloroperoxybenzoic acid (70% purity, 0.10 g, 0.42 mmol, 2.0 eq.), portion by portion. The resulting mixture was stirred at room temperature for 12 h, then diluted with DCM (10 mL). The resulting mixture was washed with aqueous NaOH (2N, 10 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to give tert-butyl (1-{4-[6-(methylsulfonyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.12 g, 100%), which was used without further purification: UPLC-MS (Procedure 3): RT = 1.38 min; m/z (rel. intensity) 519 (100, (M+H)<+>); ES-m/z (rel. intensity) 517 (10, (M-H) ).

Example for Intermediate lnt-27:

2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylic acid

To a solution of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-4 (2.00 g, 3.90 mmol), in MeOH (50 mL) was added aqueous NaOH (10%, 10 mL). The resulting mixture was stirred at room temperature for 24 h, and then diluted with water (100 mL). The pH of the resulting mixture was adjusted to a value of 4 with the help of an aqueous solution of HCl (2N). The resulting crystals were collected, washed with water, and dried at 40°C to give 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic

acid (1.50 g, 79%) which was used without further purification:

UPLC-MS (Procedure 3): RT = 0.77 min; m/z (rel. intensity) 485 (100, (M+H)<+>), 969 (40, (2M+H)<+>); ES- m/z (rel. intensity) 439 (60 (M-CO 2 H)-), 483 (100, (M-H)-), 967 (20, (M-H)').

Example for Intermediate lnt-28:

Methyl 2-(4-{1-[{tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylate

A mixture of 2-(4-{1 -[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid, which was prepared in a manner analogous to that described in Example for Intermediate lnt-27 (0.075 g, 0.16 mmol), cesium carbonate (0.15 g, 0.46 mmol, 3.0 equiv.) and methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv.) in DMF (2 mL) was stirred at room temperature for 2 days, after which an additional amount of methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv.) was added, and the mixture was heated at 50°C for 3 h. The resulting mixture was treated with water (25 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organics were dried (Na2SO4 free) and concentrated under reduced pressure to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.087 g, 113%) which was used without further purification: UPLC-MS (Procedure 3): RT = 1.46 min; m/z (rel. intensity) 499 (100, (M+H)<+>), 997 (60, (2M+H)<+>).

Example for Intermediate lnt-29:

tert-butyl (1-{4-[6,8-bi(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazine-2-

yl]phenyl}cyclobutyl)carbamate

A mixture of tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6 (0.25 g, 0.42 mmol), (4-fluorophenyl)boronic acid (0.12 g, 0.84 mmol, 2.0 eq.), 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride (0.034 g, 0.042 mmol, 0.1 eq.) and sodium carbonate (0.13 g, 1.25 mmol, 3.0 eq.) in a mixture of water (0.6 mL) and dioxane (4.5 mL) was irradiated in a microwave at 110°C during 60 min. The resulting reaction mixture was added to water (25 mL). The aqueous mixture was extracted with DCM (3 x 25 mL). The combined organic phases were washed with aqueous NaOH (2N), dried (Na2SO4 anhydrous) and concentrated under reduced pressure to give crude tert-butyl (1-{4-[6,8-bi(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.39 g) which was used without further purification: UPLC-MS (Procedure 3): RT = 1.84 min; m/z (rel. intensity) 629 (100, (M+H)<+>); ES-m/z (rel. intensity) 673 (100, (M-H+HCO2H)-).

Example for Intermediate lnt-30:

tert-butyl {1 -[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenyl-imidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate

A mixture of 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid, which was prepared in a manner analogous to that described in Example for Intermediate lnt-27 (0.40 g, 0.82 mmol), 0,N-dimethylhydroxylamine hydrochloride (0.12 g, 1.24 mmol, 1.5 eq.), PYBOP (0.54 g, 1.03 mmol, 1.25 eq.) and N,N-diisopropylethylamine (0.9 mL, 4.95 mmol, 6.0 eq.) in DMF (15 mL) was stirred at room temperature for 21 h. The resulting mixture was added to ice water (50 mL). The aqueous mixture was extracted with EtOAc (4 x 25 mL). The combined organic phases were washed sequentially with water (25 mL) and saturated aqueous NaCl (25 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting brown oil (1.48 g) was purified by MPLC (Biotage Isolera; 25 g feed SNAP, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 6.0 min, 50% hexane / 50% EtOAc 6.5 min, gradient to 10% hexane / 90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 4.5 min) which gives tert-butyl {1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.25 g, 57%): UPLC-MS (Procedure 3): RT = 1.40 min; m/z (rel. intensity) 528 (100, (M+H)<+>); ES-m/z (rel. intensity) 526 (10, (M-H+HCO2H) ).

Example for intermediate lnt-31: tert-butyl (1-{4-[6-(4-acetylphenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

To a solution of tert-butyl {1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-30 (0.25 g, 0.47 mmol), in THF (10 mL) at 0 °C under an argon atmosphere was added methylmagnesium chloride (3M in THF, 0.40 mL, 1.19 mmol, 2.5 equiv.), portionwise through the septum. The resulting mixture was stirred at 0°C and at room temperature for 5 h. More methylmagnesium chloride (3M in THF, 0.16 mL, 0.48 mmol, 1.0 eq.) was added, and the resulting mixture was stirred for 12 h. The resulting mixture was added to a saturated aqueous solution of ammonium chloride (25 mL). The aqueous mixture was extracted with EtOAc (3 x 25 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting yellow oil (0.23 g) was purified by MPLC (Biotage Isolera; 10 g feed SNAP, 100% hexane 2.0 min, gradient to 50% hexane / 50% EtOAc 2.0 min, 50% hexane / 50% EtOAc 2.0 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 21.0 min) to give tert-butyl (1-{4-[6-(4-acetylphenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.053 g, 23%): UPLC-MS (Procedure 3): RT = 1.51 min; m/z (rel. intensity) 483 (100, (M+H)<+>), 965 (80, (2M+H)<+>); ES- m/z (rel. intensity) 481 (10, (M-H)-).

Example for Intermediate lnt-32:

tert-butyl {1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate

To a mixture of tert-butyl {1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-14.6 (0.136 g, 0.26 mmol), and 5% palladium on carbon (0.026 g) in DMF (1 mL) was added a solution of sodium formate (0.18 g, 2.6 mmol, 10.0 equiv.) in water (0.4 mL). The resulting mixture was stirred at 80° C. for 3 h, then diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The resulting solution was filtered through a membrane filter and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g SNAP feed, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 4.0 min, 80% hexane / 20% EtOAc 2.5 min, gradient to 70% hexane / 30% EtOAc 2.5 min, 70% hexane / 30% EtOAc 9.6 min) to give tert-butyl {1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 93%): UPLC-MS (Procedure 3): RT = 1.65 min; m/z (rel. intensity) 483 (100, (M+H)<+>), 965 (60, (M+H)<+>) ; ES- m/z (rel. intensity) 481 (10, (M-H)").

Example for Intermediate lnt-32:

tert-butyl {1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-2-

yl)phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A] (237 mg, -80% purity, 0.430 mmol, 1.0 equiv), 6-chloro-4,5-dimethylpyridazin-3-amine (CAS-No. 76593-36-7, 67.2 mg, 0.430 mmol, 1.0 eq.) and N,N-diisopropylethylamine (70 µl, 0.430 mmol, 1.0 eq.) in butyronitrile (2.6 mL) was heated for 17 h at 125° C. After cooling, the mixture was partitioned between DCM and water, stirred vigorously, and filtered through filter paper that is covered with silicone. The filtrate was concentrated in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 25 g batch SNAP: hexane/EtOAc, 9/1 -> hexane/EtOAc, 3/2) to give 185 mg (78% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.68 min; m/z = 504 (M+H)+.

Example for Intermediate lnt-33:

Methyl 6-amino-4,5-dimethylpyridazine-3-carboxylate

A mixture of 6-chloro-4,5-dimethylpyridazin-3-amine (CAS-No. 76593-36-7, 1.00 g, 6.35 mmol, 1.0 eq.), [1,1,-bi-(diphenylphosphino)ferrocene]-palladium(ll) dichloride (1.04 g, 1.27 mmol, 0.2 eq.) and triethylamine (973 ul, 6.98 mmol, 1.1 eq.) was autoclaved (90 mL) and dissolved in 11.3 mL MeOH/THF (10/1).

The autoclave was flushed with carbon monoxide (3x), and then the pressure was increased to 9 bar with the help of carbon monoxide. The reaction mixture was stirred for 30 min at RT. Carbon monoxide was released, and the autoclave was then degassed using high vacuum. The pressure of the autoclave was again increased to 9 bar with the help of carbon monoxide, and it was subsequently heated to 100° C. During the reaction, the consumption of carbon monoxide was monitored (reduction of CO pressure). The autoclave was cooled to °C, and after releasing the carbon monoxide, it was flushed with inert gas. The reaction mixture was filtered through a small pad of Celite. The crude mixture was purified by MPLC (Biotage Isolera; 50 g batch SNAP: DCM -> DCM/ethanol, 95/5) to give 1.28 g (95% yield) of the title compound in 85% purity (UPLC, area-%).

UPLC-MS (Procedure 2): RT = 0.62 min; m/z = 182 (M+H)<+>.

Example for Intermediate lnt-34: tert-butyl {1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-2-

1-phenyl]cyclobutyl}carbamate

Step 1: 6-methoxy-4,5-dimethylpyridazin-3-amine

6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-No. 76593-36-7, 500 mg, 3.17 mmol, 1.0 equiv.) in 14.51 ml of a 25% solution (w/w) of sodium methylate in MeOH was heated for 1 h at 130°C using a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried (anhydrous Na2SO4). Volatile components are

removed using a rotary evaporator, and the crude mixture was purified using an MPLC (Biotage Isolera; charge of 25 g SNAP NH2: hexane -

>hexane/EtOAc, 1/1) to give 250 mg (49% yield) of the title compound.

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 1.98 (s, 3H), 2.00 (s, 3H), 5.49 (s, 3H), NH2 not obtained.

Step 2: tert-butyl {1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazine-2-

yl)phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A] (391 mg, -80% purity, 0.710 mmol, 1.0 eq.), 6-methoxy-4,5-dimethylpyridazin-3-amine (which was prepared in a manner analogous to described in Example for Intermediate lnt-34, Step 1, 108 mg, 0.710 mmol, 1.0 eq.) and N,N-diisopropylethylamine (140 µl, 0.780 mmol, 1.1 eq.) in butyronitrile (4.9 mL) was heated for 3 h at 120° C. After cooling, the reaction mixture was concentrated in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 25 g batch SNAP: hexane/EtOAc, 9/1 -> hexane/EtOAc, 2/3) to give 105 mg (28% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.68 min; m/z = 499 (M+H)<+>.

Example for Intermediate lnt-35:

tert-butyl (1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]-pyridazine-2-

yl]phenyl}cyclobutyl)carbamate

Step 1: 4,5-dimethyl-6-(methylsulfanyl)pyridazin-3-amine 6-chloro-4,5-dimethylpyridazin-3-amine (CAS-No. 76593-36-7, 400 mg, 2.54 mmol, 1.0 eq.) and sodium methanethiolate (196 mg, 2.79 mmol, 1.1 eq.) in 10.4 ml of ethanol. were heated for 1 h at 130°C using a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through Whatman filter paper and the volatile components were removed in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 50 g batch SNAP: DCM/ethanol, 95/5 - >DCM/ethanol, 4/1) to give 182 mg (21% yield) of the title compound in 50% purity (UPLC, area-%). UPLC-MS (Procedure 2): RT = 0.76 min; m/z = 170 (M+H)+. Step 2: tert-butyl (1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenyl-imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A] (540 mg, -80% purity, 0.970 mmol, 1.0 eq.), 4,5-dimethyl-6-(methylsulfanyl)-pyridazin-3-amine (which was prepared in a manner analogous to that described in Example for Intermediate lnt-35, Step 1, 181 mg, -50% purity, 1.07 mmol, 1.1 eq.) and N,N-diisopropylethylamine (170 µl, 0.970 mmol, 1.1 eq.) in butyronitrile (4.7 ml) was heated for 4 h at 125° C. After cooling, the reaction the mixture is concentrated in vacuo. The crude mixture was purified by preparative HPLC (reverse phase) to give 105 mg (19% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.74 min; m/z = 516 (M+H)+.

Example for Intermediate lnt-36:

tert-butyl {1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-2-

yl)phenyl]cyclobutyl}carbamate

Step 1: 6-ethoxy-4,5-dimethylpyridazin-3-amine

6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-No. 76593-36-7, 500 mg, 3.17 mmol, 1.0 equiv.) and sodium ethanolate in ethanol (16 ml, 21 w/w-%, 53.9 mmol, 17 equiv.) were heated for 2 h at 130°C using a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through a Whatman filter paper, and the volatile components were removed in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 28 g NH2 charge: hexane -> hexane/EtOAc, 1/1) to give 267 mg (50% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 0.78 min; m/z = 168 (M+H)<+>.

Step 2: tert-butyl {1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazine-2-

yl)phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A] (300 mg, -80% purity, 0.540 mmol, 1.0 eq.), 6-ethoxy-4,5-dimethylpyridazin-3-amine (which was prepared in a manner analogous to which is described in Example for Intermediate lnt-36, Step 1, 124 mg, -80% purity, 0.590 mmol, 1.1 eq.) and N,N-diisopropylethylamine (100 µl, 0.590 mmol, 1.1 eq.) in butyronitrile (3.3 mL) was heated for 3.5 h at 125° C. After cooling, the reaction mixture is concentrated in vacuo. Rough the mixture was purified by preparative MPLC (Biotage Isolera; 50 g batch SNAP: hexane/EtOAc, 9/1 -> hexane/EtOAc, 1/1) to give 220 mg (70% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.74 min; m/z = 514 (M+H)<+>.

Example 1:

1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutane-amine

To a mixture of tert-butyl {1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-1 (200 mg, 0.440 mmol, 1.0 equiv.), a solution in DCM (2.2 mL) and methanol (1.8 mL) was added. of 4M hydrogen chloride in dioxane (2.2 ml, 8.80 mmol, 20.0 equiv.), and the mixture was stirred overnight at RT. The mixture was poured into ice and brought to the alkaline region with aqueous sodium hydroxide solution (2N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was carried out by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 130 mg (83% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.20 min; m/z = 355.68 (M+H).

1H-NMR (400 MHz, MeOD): δ [ppm] = 1.96 (m, 1H), 2.24 (m, 1H), 2.54-2.64 (m, 2H), 2.67 (s, 3H), 2.70-2.84 (m, 2H), 7.49-7.65 (m, 7H), 7.66-7.71 (m, 2H), 7.80 (d, 1H), 8.32 (d, 1H), NH2 not obtained.

Example 2:

1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine

To a mixture of tert-butyl {1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-2 (300 mg, 0.608 mmol, 1.0 equiv.), in DCM (3.9 mL) and MeOH (2.5 mL) was added a solution of 4M hydrogen chloride in dioxane (3.0 mL, 12.2 mmol, 20.0 equiv.), and the mixture was stirred overnight at rt. The mixture was poured into ice, basified with aqueous sodium hydroxide (2N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was carried out by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 119 mg (52% yield) of the title compound.

UPLC-MS (Procedure 4): RT = 1.37 min; m/z = 369.29 (M+H).

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 1.18 (t, 3H), 1.59 (m, 1H), 1.82-2.20 (m, 5H), 2.25-2.39 (m, 2H), 2.73 (q, 2H), 7.20 (d, 1H), 7.31-7.38 (m, 2H), 7.39-7.56 (m, 7H), 8.06 (d, 1H).

Example 3:

1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}-cyclobutanamine

To a mixture of tert-butyl (1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-3 (680 mg, 1.177 mmol, 1.0 eq.), in DCM (7.6 mL) and methanol (4.8 mL) was added. a solution of 4M hydrogen chloride in dioxane (5.9 mL, 23.5 mmol, 20.0 equiv.) was added, and the mixture was stirred overnight at rt. The mixture was poured into ice, basified with aqueous sodium hydroxide (2N) and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was carried out by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 440 mg (92% yield) of the title compound.

UPLC-MS (Procedure 4): RT = 1.40 min; m/z = 393.58 (M-NH2)<+>.

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 1.60 (m, 1H), 1.85-2.25 (m, 5H), 2.27-2.39 (m, 2H), 7.40 (d, 2H), 7.45-7.61 (m, 7H), 7.67 (d, 1H), 8.46 (d, 1H).

Example 4:

Ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

To a mixture of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-4 (0.96 g, 1.87 mmol), in DCM (12.0 ml) and methanol (7.6 ml) was added a solution of 4M hydrochloric acid in dioxane (9.4 ml) and the mixture was stirred for 2 h at RT. The mixture was poured into ice, basified with aqueous sodium hydroxide (2N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. The reaction was repeated with the help of 2.5 g of carbamate, and the crude products from both reactions were combined. Purification was carried out by silica gel chromatography (elution gradient: DCM:ethanol, 95:5 to DCM:ethanol, 8:2) giving two fractions of the title compound (0.8 g, 88% purity & 1.6 g, 93% purity).

UPLC-MS (Procedure 3): RT = 0.97 min; m/z = 413.44 (M+H).

Example 5:

2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide

A mixture of ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate, which was prepared in a manner analogous to that described in Example 4, (1.00 g, 93% purity), and ammonia (17.3 mL of a 7M solution in methanol) was heated at 130° C. under microwave irradiation for 5 h. Volatile components were removed by distillation under reduced pressure. Crystallization from methanol/diisopropyl ether gave the title compound (672 mg, 72% yield) as a yellow solid.

UPLC-MS (Procedure 2): RT = 0.99 min; m/z = 366.59 (M-NH2).

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 8.26 (d, 1H), 7.87 (br s, 1H), 7.69 (d, 1H), 7.61-7.63 (m, 2H), 7.55-7.57 (m, 3H), 7.44-7.53 (m, 3H), 7.39 (d, 2H), 2.29-2.36 (m, 2H), 1.89-2.06 (m, 5H), 1.55-1.65 (m, 1H).

Example 6:

1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutane-amine

To a mixture of tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-5 (550 mg, 1.17 mmol), in DCM (7.5 mL) and MeOH (0.8 mL) was added a 4M solution of hydrogen chloride in dioxane (5.8 ml, 23.4 mmol, 20.0 equiv.), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice, basified with aqueous sodium hydroxide (2N), and extracted with EtOAc (3 x 25 mL). The combined organic phases were washed, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 100 g feed SNAP: 100% DCM 3.5 min, gradient to 95% DCM / 5% MeOH 1 min, 95% DCM / 5% MeOH 3.5 min, gradient to 90% DCM / 10% MeOH 1 min, 90% DCM / 10% MeOH 4.5 min) which gives 1-[4-(6-Methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (379 mg, 83% yield): UPLC-MS (Procedure 3): RT = 1.28 min; m/z (rel. intensity) 371 (95, (M+H)<+>).

1H-NMR (DMSO-de): δ [ppm] 1.52-1.66 (m, 1H), 1.87-2.08 (m, 3H), 2.05-2.28 (br m, 2H), 2.28-2.38 (m, 2H), 3.79 (s, 3H), 6.91 (d, J=9.6 Hz, 1H), 7.35 (d, J=8.7Hz, 2H), 7.40-7.53 (m, 3H), 7.49 (d, 8.5 Hz, 2H), 7.57 (ddm, J=8.3, 1.5 Hz, 2H), 8.05 (d, J=9.6 Hz).

Example 7:

1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a solution of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-7 (100 mg, 0.18 mmol), in dioxane (4 mL) was added trifluoromethanesulfonic acid (0.61 mL, 1.8 mmol, 10.0 equiv.), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice water, basified with aqueous sodium hydroxide (2N), and extracted with EtOAc (3 x 25 mL). The combined organic phases were washed, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified with the help of MPLC (Biotage

Isolator; 10 g SNAP charge: 100% DCM 4.0 min, gradient to 95% DCM / 5% MeOH 1 min, 95% DCM / 5% MeOH 3.5 min, gradient to 90% DCM /10% MeOH 1 min, 90% DCM / 10% MeOH 3.5 min, gradient to 80% DCM / 20% MeOH 6 min, 80% DCM / 20% MeOH 4.7 min) which gives the material (40 mg) which was used without additional purification by preparative HPLC (VWaters Autopurification System equipped with a pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424 and SQD 3001 using an Xselect CSH C185 uM 100x30 mm column; 60% water with 1% HCO2H / 40% methanol, 1 min, gradient to 10% water with 1% HCO2H / 90% methanol, 7 min) to give 1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (15 mg, 18%): UPLC-MS (Procedure 3): RT = 1.32 min; m/z (rel. intensity) 432 (95, (M+H-17)<+>), 449 (60, (M+H)<+>).

1H-NMR (DMSO-de): δ [ppm] 1.55-1.65 (m, 1H), 1.90-2.00 (m, 1H), 2.03-2.11 (m, 2H), 2.30-2.38 (m, 2H), 4.10 (s, 3H), 7.03 (s, 1H), 7.36 (d, J=8.6Hz, 2H), 7.45-7.54 (m, 7H).

Example 8: 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid

Aqueous sodium hydroxide (3N, 0.63 mL, 1.89 mmol, 3.0 equiv) was added to a solution of ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate, which was prepared in a manner analogous to that described in Example 4 (260 mg, 0.63 mmol), in methanol (1.5 mL), and the resulting mixture was stirred at 50°C for 1 h. The resulting mixture was added to ice water, basified with aqueous citric acid (10%), and washed with DCM (3 x 25 mL). The aqueous phase was brought into the base area and its pH was adjusted to a value of 4 with the help of hydrochloric acid (1N). The precipitate was collected by filtration, washed with water and dried under high vacuum overnight to yield 218 mg (88% yield) of the title compound.

UPLC-MS (Procedure 1): RT = 0.71 min; m/z (ESneg) = 383 (M-H)-.

1H-NMR (DMSO-de, + 1 drop TFA-d): δ [ppm] 1.77 (m, 1H), 1.10 (m, 1H), 2.40-2.64 (m, 4H, partially masked by solvent signal), 7.40-7.60 (d, 7H), 7.68 (d, 2H), 7.78 (d, 1H), 8.30 (d, 1H), 8.50 (m, 1H).

Example 9:

1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a solution of tert-butyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-7 (0.18 g, 0.37 mmol), in methanol (2.2 mL) and DCM (3.5 mL) was added hydrogen chloride (4M in dioxane, 1.8 mL, 7.3 mmol, 20.0 equiv), and the resulting mixture was stirred at room temperature for 20 h. The resulting mixture was added to ice water, basified with aqueous sodium hydroxide (2N), and extracted with EtOAc (3 x 25 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g feed SNAP: 100% DCM 6.0 min, gradient to 95% DCM / 5% MeOH 4 min, 95% DCM / 5% MeOH 5 min, gradient to 90% DCM / 10% MeOH 3.5 min) which gives 1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.11 g, 79%): UPLC-MS (Procedure 3): RT = 1.31 min; m/z (rel. intensity) 384 (100, (M+H-17)<+>), 401 (70, (M+H)<+>).

1H-NMR (DMSO-de): 5 [ppm] 1.52-1.65 (m, 1H), 1.88-2.07 (m, 5H), 2.27-2.38 (m, 2H), 3.77 (s, 3H), 4.03 (s, 3H), 6.40 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.39-7.50 (m, 5H), 7.51-7.56 (m, 2H).

Example 10: 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]-pyridazine-6-carboxamide

To a solution of 2-(4-{1 -[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylamide, which was prepared in a manner analogous to that described in Example for Intermediate lnt-10 (0.095 g, 0.18 mmol), in MeOH (1 mL) and DCM (1.8 mL) was added hydrogen chloride (4M in dioxane, 0.9 mL, 3.7 mmol, 20.0 equiv.), and the resulting mixture was stirred at room temperature for 3 days. The resulting mixture was added to ice water, basified with aqueous sodium hydroxide (2N), and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified with the help of preparative HPLC (VWaters Autopurification System equipped with pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424 and SQD 3001 using an Xselect CSH C185 uM 100x30 mm column; 60% water with 1% HCO2H / 40% MeOH 1 min, gradient up to 10% water with 1% HCO2H / 90% MeOH 7 min) to give 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide (0.020 g, 31%): UPLC-MS (Procedure 3): RT = 1.03 min; m/z (rel. intensity) 397 (100, (M+H-17)<+>), 414 (50, (M+H)<+>); ES- m/z (rel. intensity) 412 (70, (M-H) ).

1H-NMR (DMSO-de): δ [ppm] 1.53-1.66 (m, 1H), 1.89-2.07 (m, 5H), 2.12 (br s, 2H). 2.28-2.38 (m, 2H), 4.07 (s, 3H), 7.15 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42-7.56 (m, 6H), 7.56-7.62 (m, 2H), 7.82 (br s, 1H).

Example 11:

1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine

To a solution of tert-butyl {1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-11 (0.055 g, 0.12 mmol), in a mixture of MeOH (0.7 mL) and DCM (1.1 mL) was added concentrated aqueous HCl. (approx. 12N, 0.6 mL). The resulting mixture was stirred at room temperature for 60 h, and then poured into ice water (15 mL). The resulting mixture was basified with 2N NaOH solution and then extracted with EtOAc (3 x 20 mL). The combined organic phases were dried (Na 2 SO 4 anhydrous), and concentrated under reduced pressure. The resulting oil (34 mg) was purified by preparative HPLC (Agilent Prep 1200, equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C185 pm 100x30 mm column; gradient from 70% water with 0.2% NH3/ 30% CHsCN to 40% water with 0.2% NH3 / 60% CH3CN over 17.5 min, gradient from 40% water with 0.2% NH3 / 60% CHsCN to 100% CHsCN over 2.5 min) to give 1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.021 g, 48% yield): UPLC-MS (Procedure 3): RT = 1.18 min; m/z (rel. intensity) 371 (30, (M+H)<+>).

1H-NMR (DMSO-de): δ [ppm] 1.52-1.65 (m, 1H), 1.87-2.13 (m, 5H), 2.12 (br s, 2H). 2.28-2.37 (m, 2H), 4.06 (s, 3H), 6.73 (d, J=5.7 Hz 1H), 7.35 (d, J=8.7 Hz, 2H), 7.43-7.50 (m, 5H), 7.53, (d, J=8.7 Hz, 2H).

The following examples were prepared in a manner analogous to that of Example 11 by reacting the appropriate carbamate intermediates with concentrated aqueous HCl.

Example 17:

1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutane-amine

To a solution of tert-butyl {1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6.2 (0.075 g, 0.15 mmol), in MeOH (0.65 mL) and DCM (1.0 mL) was added hydrogen chloride (4M in dioxane, 0.8 ml, 3.2 mmol, 20.0 equiv.), and the resulting mixture was stirred at room temperature for 19 h. The resulting mixture was added to ice water (50 mL), brought to the base region with aqueous sodium hydroxide (2N), and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was re-crystallized with diisopropyl ether to give 1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.040 g, 68%): UPLC-MS (Procedure 3): RT = 1.32 min; m/z (rel. intensity) 358 (100, (M+H-17)<+>), 375 (60, (M+H)<+>).

1H-NMR (DMSO-de): δ [ppm] 1.52-1.65 (m, 1H), 1.87-2.07 (m, 3H), 2.16 (br s, 2H). 2.27-2.37 (m, 2H), 7.35-7.40 (m, 3H), 7.48-7.56 (m, 7H), 8.25 (d, J=9.4 Hz, 1H).

Example 18:

1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

Trifluoromethanesulfonic acid (0.61 ml, 1.8 mmol, 10.0 equiv.), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice water, basified with aqueous sodium hydroxide (2N), and extracted with EtOAc (3 x 25 mL). The combined organic phases were washed, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g feed SNAP: 100% DCM 3.0 min, gradient to 95% DCM / 5% MeOH 1 min, 95% DCM / 5% MeOH 2.5 min, gradient to 90% DCM /10% MeOH 3 min, 90% DCM /10% MeOH 3.5 min) which gives 1 -[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.022 g, 70%): UPLC-MS (Procedure 3): RT = 1.32 min; m/z (rel. intensity) 380 (95, (M+H-1 7)<+>), 397 (70, (M+H)<+>).

1H-NMR (DMSO-de): 6 [ppm] 1.54-1.64 (m, 1H), 1.89-2.10 (m, 5H), 2.28-2.36 (m, 2H), 4.11 (s, 3H), 5.63 (d, J=11.4 Hz, 1H), 6.27 (d, J=17.7Hz, 1H), 6.64 (dd, J=17.7, 11.1 Hz, 1H), 7.06 (s, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.42-7.53 (m, 8H).

The following examples were prepared in a manner analogous to that of Example 18 by reacting the appropriate carbamate intermediates with trifluoromethanesulfonic acid.

Example 50:

1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a mixture of tert-butyl {1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-32 (179 mg, 0.360 mmol, 1.0 equiv), in DCM (2.29 mL) and MeOH (1.44 mL) was added to a solution of 4M hydrogen chloride in dioxane (1.78 mL, 7.12 mmol, 20.0 equiv.), and the mixture was stirred overnight at rt. The mixture was poured into ice, basified with aqueous sodium hydroxide (2N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 10 g charge

SNAP: DCM - >DCM/ethanol, 95/5) to give 64 mg (44% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.48 min; m/z = 403 (M+H)<+>.

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 1.59 (m, 1H), 1.93 (m, 1H), 2.02 (m, 2H), 2.11 (br s, 2H), 2.31 (m, 2H), 2.35 (s, 3H), 2.64 (s, 3H), 7.37 (d, 2H), 7.46-7.52 (m, 5H), 7.54 (d, 2H).

Example 51:

Methyl 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-

carboxylate

A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [which was prepared in a manner analogous to that described in Example Intermediate lnt-1-A] (630 mg, -90% purity, 1.28 mmol, 1.0 eq.), methyl 6-amino-4,5-dimethylpyridazine-3-carboxylate [which was prepared in a manner analogous to which is described in Example for Intermediate lnt-34] (257 mg, 1.28 mmol, 1.0 eq.), N,N-diisopropylethylamine (220 µl, 1.28 mmol, 1.0 eq.) in butyronitrile (2.6 mL) was heated for 17 h at 125° C. After cooling, the mixture was partitioned between DCM and water, stirred vigorously, and filtered through filter-paper which is covered with silicone. The filtrate was concentrated in vacuo. The crude mixture was purified by preparative HPLC (reverse phase) to give 89 mg (16% yield) of the title compound, directly in the amine form.

UPLC-MS (Procedure 2): RT = 1.35 min; m/z = 427 (M+H)<+>.

1H-NMR (400 MHz, MeOD): δ [ppm] = 1.75 (m, 1H), 2.06 (m, 1H), 2.24 (m, 2H), 2.44 (s, 3H), 2.56 (m, 2H), 2.71 (s, 3H), 3.93 (s, 3H), 7.38 - 7.47 (m, 5H), 7.48-7.54 (m, 2H), 7.60 (d, 2H).

Example 52: 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazine-6-

carboxamide

A solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate [which was prepared in a manner analogous to that described in Example 51] (80 mg, -90% purity, 0.170 mmol, 1.0 equiv.) in 2.41 ml of 7N ammonia in MeOH (-100 equiv. NH3) was heated for 2 h at 130°C using a single mode microwave oven (Biotage). After cooling, the volatiles were removed in vacuo. The crude mixture was purified by MPLC (Biotage Isolera; 11 g feed SNAP NH 2 : hexane/EtOAc, 1:1 -> EtOAc) to give 54 mg (77% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.22 min; m/z = 412 (M+H)<+>.

1H-NMR (400 MHz, MeOD): δ [ppm] = 1.74 (m, 1H), 2.06 (m, 1H), 2.24 (m, 2H), 2.48 (s, 3H), 2.55 (m, 2H), 2.70 (s, 3H), 7.38-7.48 (m, 5H), 7.52-7.57 (m, 2H), 7.60 (d, 2H).

Example 53: 1-[4-(6-Methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a solution of methyl tert-butyl {1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate [which was prepared in a manner analogous to that described in Example for Intermediate lnt-34] (80 mg, -80% purity, 0.160 mmol, 1.0 eq.), in DCM (1.03 ml) and MeOH (0.65 ml) was added a solution of 4M hydrogen chloride in dioxane (0.80 ml, 3.21 mmol, 20.0 equiv.), and the mixture was stirred overnight at RT. The mixture was poured into ice, basified with aqueous sodium hydroxide (2N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. The crude mixture was purified by preparative HPLC to give 44 mg (62% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.48 min; m/z = 399 (M+H)<+>.

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 1.61 (m, 1H), 1.94 (m, 1H), 2.05 (m, 2H), 2.16 (s, 3H), 2.34 (m, 2H), 2.52 (s, 3H), 3.81 (s, 3H), 7.32-7.42 (m, 3H), 7.45 (m, 2H), 7.51 (m, 2H), 7.55 (m, 2H), NH2 not obtained.

Example 54: 1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]-phenyljcyclobutanamine

To a mixture of tert-butyl (1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-35 (95 mg, 0.190 mmol, 1.0 equiv) in DCM (1.19 mL) and MeOH (0.75 mL) was added a solution of 4M hydrogen chloride in dioxane (0.92 mL, 3.69 mmol, 20.0 equiv.), and the mixture was stirred overnight at rt. The mixture was poured into ice, brought to the base zone, treated with DCM and filtered through a phase separator. Volatile components from the organic phase were removed in vacuo to give 75 mg (94% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.55 min; m/z = 415 (M+H)<+>.

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 1.60 (m, 1H), 1.87-2.09 (m, 3H), 2.12 (br s, 2H), 2.22 (s, 3H), 2.33 (m, 2H), 2.38 (s, 3H), 2.55 (s, 3H), 7.33-7.50 (m, 5H), 7.51-7.60 (m, 4H).

Example 55: 1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a mixture of tert-butyl {1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-36 (210 mg, 0.410 mmol, 1.0 equiv), in DCM (2.64 mL) and MeOH (1.66 mL) was added a solution of 4M hydrogen chloride in dioxane (2.05 mL, 8.19 mmol, 20.0 equiv.), and the mixture was stirred overnight at rt. The mixture was poured into ice, brought to the base zone, treated with DCM and filtered through a phase separator. Volatile components from the organic phase were removed in vacuo to give 145 mg (82% yield) of the title compound.

UPLC-MS (Procedure 2): RT = 1.56 min; m/z = 414 (M+H)<+>.

1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 1.30 (t, 3H), 1.59 (m, 1H), 1.87-2.10 (m, 5H), 2.15 (s, 3H), 2.33 (m, 2H), 2.51 (s, 3H), 4.17 (q, 2H), 7.34 (m, 2H), 7.37-7.50 (m, 4H), 7.50-7.56 (m, 3H).

Example 56:

Methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)-imidazo[1,2-b]pyridazine-6-carboxylate

A solution of 1 -{4-[6-chloro-3-phenyl-8-(1 H -pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine, which was prepared in a manner analogous to that described in Example 19 (0.59 g, 1.34 mmol), in MeOH (2.2 ml) and THF (0.2 ml) was added in an autoclave. 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride (0.22 g, 0.27 mmol, 0.20 eq.) and triethylamine (0.20 ml, 1.47 mmol, 1.1 eq.). The autoclave was washed with CO (approximately 5 bar) three times, and then the pressure was increased with the help of CO (5.2 bar), everything was mixed at room temperature for 30 min, and then it was briefly placed in an atmosphere of reduced pressure (0.06 bar). The autoclave was then pressurized with the help of CO (5.9 bar at 20° C), everything was heated to 110° C, and then mixed at the same temperature for 22 h. The solution was then concentrated under reduced pressure. The material was then purified by MPLC (Biotage Isolera; 25 g SNAP feed: 100% DCM 2.0 min, gradient to 95% DCM / 5% MeOH 1.0 min, 95% DCM / 5% MeOH 2.5 min, gradient to 90% DCM / 10% MeOH 1.5 min, 90% DCM / 10% MeOH 4.5 min) which gives crude material (0.45 g). Part of the material was further purified by preparative HPLC (Agilent Prep 1200 equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using XBrigde C18 5um 100x30 mm column; gradient from 70% water with 0.2% NH3/ 30% CHsCN to 40% water with 0.2% NH3/ 60% CH3CN over 17.5 min, gradient from 40% water with 0.2% NH3 / 60% CH3CN to 100% CH3CN over 2.5 min) to give methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate (0.013 g, 17% based on purified 11%): UPLC-MS (Procedure 3): RT = 1.28 min; m/z (rel. intensity) 448 (100 (M+H-17)<+>), 465 (80, (M+H)<+>); ES- m/z (rel. intensity) 463 (40, (M-H)").

1H-NMR (d6-DMSO): δ 1.56-1.67 (m, 1H), 1.91-2.00 (m, 1H), 2.02-2.11 (m, 2H), 2.32-2.39 (m, 2H), 3.88 (s, 3H), 7.42 (d, J=8.6 Hz, 2H). 7.51-7.58 (m, 5H), 7.65 (d, J=8.3 Hz, 2H), 7.77 (d, J=2.3Hz, 1H), 7.98 (brs, 1H), 8.28 (s, 1H).

The following examples were prepared in a manner analogous to that of Example 56 by reacting the appropriate halide with MeOH and CO in the presence of 1,1'-bi(diphenylphosphino)ferrocenepalladium(II) dichloride.

Example 59:

tert-butyl {1-[4-(8-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate

A solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate, which was prepared in a manner analogous to that described in Example 31 (0.040 g, 0.10 mmol), in a solution of ammonia in MeOH (7N, 0.7 ml, 5.0 mmol, 50 equiv.) was irradiated in a microwave oven at 130° C for 90 min. The resulting mixture was concentrated under reduced pressure. The resulting material was triturated with diisopropyl ether to give tert-butyl {1-[4-(8-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.025 g, 60%): UPLC-MS (Procedure 3): RT = 1.17 min; m/z (rel. intensity) 367 (100, (M+H-17)<+>), 384 (70, (M+H)<+>).

1H-NMR (DMSO-de): 5 [ppm] 1.54-1.69 (m, 1H), 1.90-2.01 (m, 1H), 2.03-2.13 (m, 2H), 2.31-2.40 (m, 2H), 7.41 (d, J=8.5Hz, 2H), 7.48-7.56 (m, 5H), 7.61 (d, J=8.5Hz, 2H), 7.75 (d, J=4.7 Hz, 1H), 8.41 (br s, 1H), 8.63 (d, J=4.7 Hz, 1H), 9.25 (br s, 1H).

The following examples were prepared in a manner analogous to that of Example 59 by reacting the corresponding ester with ammonia.

The following examples were prepared in a manner analogous to that of Example 59 by reacting the corresponding ester with methylamine. The following examples were prepared in a manner analogous to that of Example 59 by reacting the corresponding ester with ethylamine.

Example 67:

2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]-pyridazine-6-carboxylic acid

To a solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate, which was prepared in a manner analogous to that described in Example 56 (0.19 g, 0.41 mmol), in MeOH (5 mL) was added aqueous NaOH (10%, 0.65 mL, 1.64 mmol, 4.0 eq.). The resulting mixture was stirred at room temperature for 48 h. Water (10 mL) was added to the resulting mixture, and the pH was adjusted to 4 with aqueous 2N HCl. The resulting precipitate was collected by filtration and recrystallized from dimethyl sulfoxide to give 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic

acid (0.012 g, 6%).

UPLC-MS (Procedure 3): RT = 0.70 min; m/z (rel. intensity) 434 (40 (M+H-17)<+>), 451 (100, (M+H)<+>); ES- m/z (rel. intensity) 449 (70, (M-H)"), 899 (50, (2M-H)").

1H-NMR (DMSO-de): 5 [ppm] 1.70-1.83 (m, 1H), 2.04-2.17 (m, 1H), 2.03-2.13 (m, 2H), 2.53-2.64 (m, 3.5 H, partially obscured by solvent signal), 7.50 (d, J=8.5 Hz, 2H), 7.52-7.58 (m, 5H), 7.75-7.80 (m, 3H), 7.97 (d, J=2.3 Hz, 1H), 8.30 (s, 1H).

Example 68: 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]-pyridazine-6-

carboxamide

To a solution of 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid, which was prepared in a manner analogous to that described in Example 8 (0.15 g, 0.39 mmol), and methylamine (2M in THF, 1.43 mL, 2.93 mmol, 7.5 equiv) in DMF (1 mL) was added PYBOP. (0.22 g, 0.43 mmol 1.10 eq.) and N,N-diisopropylethylamine (0.27 mL, 1.56 mmol, 4.0 eq.). The resulting mixture was stirred at room temperature for 25 h, and then treated with water (10 mL). The resulting aqueous mixture was extracted with EtOAc (4x15 mL). The combined organic phases were washed with water (2 x

15 mL), dried (Na2SO4 anhydrous) and concentrated under reduced pressure. The resulting material was triturated with MeOH to give 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide (0.085 g, 55%): UPLC-MS (Procedure 3): RT = 1.09 min; m/z (rel. intensity) 381 (100 (M+H-17)<+>), 398 (70, (M+H)<+>), 795 (10, (2M+H)<+>); ES- m/z (rel. intensity) 396 (40, (M-H)). 1H-NMR (DMSO-de): h [ppm] 1.55-1.66 (m, 1H), 1.89-2.08 (m, 5H), 2.28-2.38 (m, 2H), 2.78 (d, J=4.7 Hz, 3H), 7.38 (d, J=8.3 Hz, 2H), 7.46-7.56 (m, 5H), 7.61 (dd, J=7.7, 1.3 Hz, 2H), 7.68 (d, J=9.4 Hz, 1H), 8.16 (brq, J=4.7 Hz, 1H), 8.26 (s, 1H).

The following examples were prepared in a manner analogous to that of Example 68 by PYBOP-assisted reaction of the appropriate carboxylic acid with the appropriate amine.

Example 72:

Methyl 3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-

yl}propanoate

Step 1: Methyl (2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-8-ii]acrylate

A solution of tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-6 (0.50 g, 0.84 mmol), methyl acrylate (0.11 ml, 1.3 mmol, 1.5 eq.) and triethylamine (0.13 ml, 0.96 mmol, 1.1 eq.) in acetonitrile (6 ml) was left under an argon atmosphere. Tri(2-tolyl)phosphine (0.043 g, 0.14 mmol, 0.17 eq.) and palladium(II) acetate (0.013 g, 0.059 mmol, 0.07 eq.) were added to said solution. The resulting mixture was irradiated in a microwave oven at 150°C for 60 min. The resulting mixture was then added to water (15 ml). The resulting mixture was extracted with EtOAc (2x25 mL). The combined organic phases were washed with water (25 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; loading of 10 g SNAP, 100% hexane 1.5 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 2.0 min, gradient to 50% hexane / 50% EtOAc 3.0 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give methyl (2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl]acrylate (0.50 g, 99%) which was used without further purification.

Step 2: Methyl 3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-8-yl}propanoate

A mixture of methyl (2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl carbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl]acrylate, which was prepared in a manner analogous to that described in Example 72, Step 1 (0.50 g, 0.83 mmol), and 10% palladium on carbon. (0.26 g) in a mixture of ethanol (14 ml) and THF (5 ml) was left in a hydrogen atmosphere at room temperature for 1 h. The resulting mixture was treated with an additional amount of 10% palladium on carbon (0.26 g) and left under a hydrogen atmosphere for 1 h. The solids were removed by filtration and washed with ethanol (20 ml). The combined organic solutions were treated with 10% palladium on carbon (0.26 g) and placed in a hydrogen atmosphere for 1 h. The solids were removed by filtration and washed with ethanol (20 ml). The combined organic solutions were concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 25 g SNAP feed, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.5 min, gradient to 74% hexane / 26% EtOAc 2.5 min, gradient to 70% hexane / 30% EtOAc 2.0 min, gradient to 50% hexane / 50% EtOAc 3.0 min, 50% hexane / 50% EtOAc 6.4 min, gradient to 25% hexane / 75% EtOAc 3.5 min, 25% hexane / 75% EtOAc 5.3 min gradient to 100% EtOAc 5.3 min, 100% EtOAc 21.2 min). The resulting material was further purified by preparative HPLC (Agilent Prep 1200 equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5um 100x30 mm column; gradient from 100% water with 0.1% HCO2H to 70% water with 0.1% HCO2H / 30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCO2H / 70% MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9 min) gives methyl 3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}propanoate (0.003 g, 1%): UPLC-MS (Procedure 3): RT = 0.97 min; m/z (rel. intensity) 410 (500 (M+H-17)<+>), 427 (60, (M+H)<+>).

1H-NMR (CD3OD): 5 [ppm] 1.76-1.89 (m, 1H), 2.04-2.1 8 (m, 1H), 2.30-2.41 (m, 2H), 2.58-2.69 (m, 2H), 2.97 (t, J=7.4 Hz, 2H), 3.40 (t, J=7.5 Hz, 2H), 3.68 (s, 3H), 7.10 (d, J=4.5 Hz, 1H), 7.41-7.47 (m, 5H), 7.48-7.53 (m, 2H), 7.65 (d, J=8.5 Hz, 2H), 8.29 (d, J=4.7 Hz, 1H).

Example 73:

1-{4-[6-Methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]-phenylcyclobutanamine

A solution of 1 -{4-[6-chloro-3-phenyl-8-(1 H -pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine, which was prepared in a manner analogous to that described in Example 19 (0.14 g, 0.32 mmol), and sodium methoxide (0.051 g, 0.95 mmol, 3.0 eq.) in MeOH (0.8 mL) was irradiated in a microwave oven at 120° C for 90 min. The resulting mixture was added to water (10 mL). The aqueous mixture was extracted with DCM (3 x 15 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g SNAP loading, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 2.5 min, 50% hexane / 50% EtOAc 3.5 min, gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) yielding an oil which was triturated with MeOH to yield 1-{4-[6-methoxy-3-phenyl-8-(1 H -pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine (0.052 g, 36%): UPLC-MS (Procedure 3): RT = 1.37 min; m/z (rel. intensity) 420 (100 (M+H-17)<+>), 437 (60, (M+H)+); ES- m/z (rel. intensity) 435 (80, (M-H)-).

1H-NMR (DMSO-de): 6 [ppm] 1.55-1.66 (m, 1H), 1.87-2.13 (m, 5H), 2.29-2.39 (m, 2H), 3.82 (s, 3H), 7.32 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.42-7.53 (m, 3H), 7.56-7.62 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.91 (br s, 1H).

The following examples were prepared in a manner analogous to that of Example 73 by reacting sodium methoxide with the appropriate halide.

The following examples were prepared in a manner analogous to that of Example 73 by reacting sodium ethoxide with the appropriate halide.

Example 77:

1-[4-(8-butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

A mixture of ethyl {1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 0.24 mmol) and potassium hydroxide (powder, 0.077 g, 1.17 mmol, 5.0 equiv) in n-butanol (2.5 mL) was heated under reflux for 24 h. The resulting mixture was cooled to room temperature and partitioned between a mixture of DCM/isopropanol solution, 4:1 (50 mL) and water (50 mL). The organic phase was washed with saturated aqueous NaCl (25 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isoler; 10 g feed SNAP: 100% DCM 4.0 min, gradient to 95% DCM / 5% MeOH 1 min, 95% DCM / 5% MeOH 3.5 min, gradient to 90% DCM / 10% MeOH 1 min, 90% DCM / 10% MeOH 3.5 min, gradient to 80% DCM / 20% MeOH 6 min, 80% DCM / 20% MeOH 4.7 min) to give 1-[4-(8-butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.013 g, 9%): 1H-NMR (DMSO-de): 5 [ppm] 0.97 (t, J=7.5 Hz, 3H), 1 .30 (t, J=7.0 Hz, 3H), 1 .49 (sext. J=7.5 Hz, 2H), 1.56-1.67 (m, 1 H), 1.83 apparent (pent, J=7.0Hz, 2H), 1.91-2.24 (m, 5H), 2.31-2.39 (m, 2H), 4.17 (q, J=7.3 Hz, 2H), 4.30 (t, J=6.6 Hz, 2H), 6.40 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.40-7.50 (m, 5H), 7.53-7.56 (m, 2H).

Example 78:

1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutane-amine

A mixture of tert-butyl {1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate, which was prepared in a manner analogous to that described in Example Intermediate lnt-6.2 (0.050 g, 0.11 mmol), and potassium hydroxide (powder, 0.050 g, 0.89 mmol, 8.5 eq.) in ethanol (0.8 ml) was irradiated in a microwave oven at 120° C for 120 min. The resulting mixture was added to ice water (10 ml). The aqueous mixture was extracted with a mixture of DCM/isopropanol solution, 4:1 (4 x 10 ml). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was purified by MPLC (Biotage Isolera; 10 g feed SNAP: 100% DCM 4.0 min, gradient to 95% DCM / 5% MeOH 1 min, 95% DCM / 5% MeOH 3.5 min, gradient to 90% DCM /10% MeOH 1 min, 90% DCM / 10% MeOH 3.5 min, gradient to 80% DCM / 20% MeOH 6 min, 80% DCM / 20% MeOH 4.7 min) to give 1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.017 g, 42%): UPLC-MS (Procedure 3): RT = 1.39 min; m/z (rel. intensity) 368 (100 (M+H-17)<+>), 385 (80, (M+H)<+>), 769 (10, (2M+H)<+>).

1H-NMR(DMSO-de): h [ppm] 1.28 (t, J=7.0 Hz, 3H), 1.53-1.65 (m, 1H), 1.87-2.08 (m, 5H), 2.27-2.33 (m, 2H), 4.18 (q, J=7.0 Hz, 2H), 6.88 (d, J=9.6 Hz, 1H), 1H), 7.35 (d, J=8.5 Hz, 2H), 7.41-7.56 (m, 7H), 8.03 (d, J=9.6 Hz, 1H).

Example 79:

2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-ol

A mixture of tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate, which was prepared in a manner analogous to that described in Example for Intermediate lnt-5 (0.25 g, 0.53 mmol), in N-methylpyrrolidone (5 ml) was heated to 100° C., then sodium sulfide was added. (0.21 g, 2.66 mmol, 5.0 equiv.), and the mixture was heated to 160° C. for 10 min. The resulting mixture was added to ice water (15 ml). The aqueous mixture was acidified with aqueous 2N HCl and then buffered with saturated aqueous sodium bicarbonate. The resulting precipitate was removed by filtration, washed with water, and dried at 50° C. in vacuo to give 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-ol (0.10 g, 53%): UPLC-MS (Procedure 3): RT = 0.61 min; m/z (rel. intensity) 340 (100 (M+H-17)<+>), 357 (90, (M+H)<+>), 713 (20, (2M+H)<+>); ES- m/z (rel. intensity) 355 (100, (M-H) ), 711 (100, (2M-H)").

1H-NMR (DMSO-de): 6 [ppm] 1.55-1.66 (m, 1H), 1.86-1.99 (m, 1H), 2.20-2.11 (m, 2H), 2.30-2.38 (m, 2H), 6.70 (d, J=9.6 Hz, 1H), 7.32 (d, J=8.3 Hz, 2H), 7.38-7.49 (m, 7H), 7.88 (d, J=9.6 Hz, 1H).

Example 80:

Methyl ({2-[4-(1 -aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-

yloxy)acetate

To a solution of 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-ol, which was obtained as described in Example 79 (0.093 g, 0.26 mmol), in DMF (2.5 ml) were added cesium carbonate (0.26 g, 0.79 mmol, 3.0 equiv.) and bromoacetic acid methyl ester. (0.03 ml, 0.31 mmol, 1.20 eq.). The resulting mixture was stirred at room temperature for 1 h, and then heated to 60°C for 3 h. The resulting mixture was diluted with water (10 ml). The aqueous mixture was extracted with EtOAc (3x10 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting material was further purified by preparative HPLC (Agilent Prep 1200 equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5um 100x30 mm column; gradient from 100% water with 0.1% HCO2H to 70% water with 0.1% HCO2H / 30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCO2H / 70% MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9 min) to give methyl ({2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}oxy)acetate (0.056 g, 49%): UPLC-MS (Procedure 3): RT = 1.21 min; m/z (rel. intensity) 412 (100 (M+H-17)<+>), 429 (60, (M+H)<+>), 857 (10, (2M+H)<+>).

1H-NMR (DMSO-de): δ [ppm] 1.54-1.68 (m, 1H), 1.86-2.11 (m, 3H), 2.30-2.39 (m, 2H), 3.56 (s, 3H), 4.81 (s, 2H), 7.03 (d, J=9.6 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.41-7.47 (m, 5H), 7.52 (d, J=8.5 Hz, 2H), 8.12 (d, J=9.6 Hz, 1H).

Biological research

The following tests may be used in order to illustrate the commercial use of the compounds of the present invention.

The samples were tested in selected bioassays, one or more times. When tested more than once, the data are reported as average values or median values, where • the average value, also referred to as the arithmetic mean, is the sum of the values obtained divided by the number of tests performed, and • the mean value is the middle number of a group of values that are arranged in ascending or descending order. If the number of values in a group is odd, the median is the middle value. If the number of values in a group is even, the median is arithmetic

the middle of the two means.

Examples were synthesized one or more times. When synthesized more than once, data from bioassays represent average values or mean values calculated with the help of groups of data obtained by testing one or more synthetic rounds.

Biological Assay 1.0: Acti Kinase Assay

The inhibitory activity of the compounds of the present invention against Akti was quantified using the Akti TR-FRET assay, as described in the following paragraphs.

Full-length His-tagged human Akti recombinant kinase was expressed in insect cells and was obtained from Invitrogen (cat. no. PV 3599). The biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used as a substrate for the kinase reaction, which can be obtained for example from Biosvnthan GmbH (Berlin-Buch, Germany).

For the assay, a 50- or 100-fold concentrated solution of the test compound in DMSO was pipetted into a small-volume 384-well black microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 µl of Akti solution in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCb, 1 mM dithiothreitol, 0.02% (v/v) Triton was added.

X-

100 (Sigma)], and the mixture was incubated for 15 min at 22°C in order to allow pre-binding of the tested compounds to the enzyme before the kinetic reaction started. Then the kinase reaction was started by adding 3 ul of adenosine-tri-phosphate solution (ATP, 16.7 uM => final conc, in 5 ul of test volume is 10 uM) and substrate (1.67 uM => final conc, in 5 ul of test volume is 1 uM) in the test buffer, and the resulting mixture was incubated for a reaction time of 60 min at 22°C. in the test, it is set depending on the activity of the enzyme lot, and it is chosen so that the test is carried out in a linear range, with typical enzyme concentrations ranging from about 0.05 ng/ul (final concentration, in 5 ul of the test volume). The reaction was stopped by adding 5 µl of a solution of HTRF detection reagent (200 nM streptavidin-XL665 [Cisbio] and 1.5 nM anti-phospho-serine antibody [Millipore, cat. # 35-001 ] and 0.75 nM LANCE Eu-W 1024 labeled anti-mouse IgG antibody [Perkin Elmer]) in aqueous EDTA solution. (100 mM EDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5). The resulting mixture was incubated for 1 h at 22°C in order to enable binding of the biotinylated phosphorylated peptide to streptavidin-XL665 and the mentioned antibodies. Subsequently, the amount of phosphorylated substrate was estimated by measuring the resonance energy transfer from the anti-mouse-IgG-Eu-chelate to streptavidin-XL665. Therefore, fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm are recorded on an HTRF reader, for example Rubvstar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-EImer). The ratio of emissions at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzymatic reaction without inhibitor = 0% inhibition, all other components for tast but no enzyme = 100% inhibition). Normally, the test compounds were tested on the same microtiter plate using 10 different concentrations ranging from 20 µM to 1 nM (20 µM, 6.7 µM, 2.2 µM, 0.74 µM, 0.25 µM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series that were prepared before the assay at the 100-fold level conc, stock solutions using 1:3 serial dilutions), where duplicate values were taken for each concentration, and IC50 values were calculated using a 4-parameter fit using in-house software.

Bioassay 2.0: Akt2 Kinase Assay

The inhibitory activity of the compounds of the present invention against Akt2 was quantified using the Akt2 TR-FRET assay, as described in the following paragraphs.

Full-length His-tagged human recombinant kinase Akt2 was expressed in insect cells, activated by PDK1, and purchased from Invitrogen (number PV 3975). The biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used as a substrate for the kinase reaction and was obtained, for example, from Biosvnthan GmbH (Berlin-Buch, Germany). For the assay, 50 or 100-fold concentrated solution of the test compound in DMSO was pipetted into a 384-well small-volume black microtiter plate (Greiner Bio-One, Frickenhausen, Germany), then 2 µl of Akt2 solution in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCb, 1 mM dithiothreitol, 0.02%] was added. (v/v) Triton X-100 (Sigma)], and the mixture was incubated for 15 min at 22°C to allow the test compounds to bind to the enzyme before starting the kinase reaction. The kinase reaction was initiated by adding 3 ul of adenosine-tri-phosphate solution (ATP, 16.7 µM => final conc, in 5 µl test volume is 10 µM) and substrate (1.67 µM => final conc, in 5 µl test volume is 1 µM) in the assay buffer, and the resulting mixture was incubated for a reaction time of 60 min at 22° C. Akt2 concentration in the assay is adjusted depending on the activity of the enzyme lot, and the one that allows the test to be carried out in a linear range was chosen, with typical enzyme concentrations ranging from about 0.2 ng/ul (final concentration, in 5 µl of the test volume). The reaction was stopped by adding 5 µl of a solution of HTRF detection reagent (200 nM streptavidin-XL665 [Cisbio] and 1.5 nM anti-phospho-serine antibody [Millipore, cat. #35-001 ] and 0.75 nM LANCE Eu-W 1024 labeled anti-mouse IgG antibody [Perkin Elmer]) in aqueous EDTA solution. (100 mM EDTA, 0.1%

(w/v), bovine serum albumin in 50 mM HEPES/NaOH pH 7.5). The resulting mixture was incubated for 1 h at 22°C in order to enable binding of the biotinylated phosphorylated peptide to streptavidin-XL665 and the mentioned antibodies. Subsequently, the amount of phosphorylated substrate was estimated by measuring the resonance energy transfer from the anti-mouse-IgG-Eu-chelate to streptavidin-XL665. Therefore, fluorescent

emissions at 620 nm and 665 nm after excitation at 350 nm were measured on a TR-FRET reader, for example Rubvstar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-EImer). The ratio of emissions at 665 nm and at 622 nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzymatic reaction without inhibitor = 0% inhibition, all other components but no enzyme = 100% inhibition). Normally, the test compounds were tested in the same microtiter plate at 10 different concentrations ranging from 20 µM to 1 nM (20 µM, 6.7 µM, 2.2 µM, 0.74 µM, 0.25 µM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before starting the assay on a 100-fold basis conc, stock solutions using serial dilutions of 1:3), where duplicate values were taken for each concentration, and IC 50 values were calculated using a 4-parameter setup using in-house software.

Preferred compounds of the present invention show in both kinase assays, Akti or Akt2: median IC 50 <5 µM or greater than 50% inhibition at 5 pM, better, median IC 50 <0.5 µM or greater than 50% inhibition at 0.5 pM, even better, median IC 50 £0.1MM or greater than 50% inhibition at 0.1 pM.

The following Table shows selected data for selected Examples of this invention.

Cell assays3.0: p-AKT1/2/3-S473, -T308, ip-4E-BP1-T70 assays

The molecular mechanism of action was investigated by a series of experiments to evaluate the inhibition of the PI3K-AKT-mTOR pathway in cell lines that are sensitive to the inhibition of the mentioned pathway, such as the KPL-4 breast tumor cell line (PIK3CAH1047R>HER2<0/E>i hormone-independent). Phospho-substrates of the PI3K-AKT-mTOR axis were used without read-outs to reflect the inhibition of the mentioned pathway. Confluency of seeded cells per well was 60-80% in 96-well plates. After overnight incubation at 37°C with 5% CO2, cells were treated with compounds and vehicle at 37°C for 2 h. Subsequently, cells were lysed in 150 µl of lysis buffer, and the levels of phospho-AKT at T308 and S473 and p-4E-BP1 at T70 sites were determined using the appropriate AlphaScreen<®>SureFire<®> assay kit (Perkin Elmer: 4E-BP1 Test Kit Cat. #TRG4E2S1 OK; Akt 1/2/3 p-Ser 473 #TGRA4S500 and Akt 1/2/3 p-Thr 308 #TGRA3S500, as well as IgG detection Kit #6760617M) as described in the manuals. All measurements were performed at least twice and confirmed by means of independent replication.

Alternatively, the pAKT-S473 assay was performed using "Akt Duplex" from the MULTI-SPOT<®>Test System (Fa. Meso Scale Discoverv, Cat.# N41100B-1) following the manufacturer's instructions. Each assay used 20 pg of protein extract, and the total content of AKT and p-AKT was measured simultaneously in one well. All measurements were performed at least twice and confirmed by means of independent replication. Values for P-AKT are shown as a percentage of P-AKT levels relative to the total-AKT content of the extracts.

The following Table shows selected data for selected Examples of this invention.

Biological test 4.0: Tumor cell proliferation tests

The compounds were tested in a cell-based assay that measures the capacity of said compounds to inhibit the proliferation of tumor cells during a 72 h exposure to the drug. Cell viability was determined using CellTiter-Glovv<®> (CTG, Promega, cat.# G7571/2/3). The CellTiter-Glo<®>Luminescent Cell Viability test is a homogeneous procedure for determining the number of viable cells in culture.

Detection is based on the application of the luciferase reaction with the aim of measuring the amount of ATP from viable cells. The amount of ATP in cells corresponds to cell viability. Within a minute after the loss of membrane integrity, cells lose the ability to synthesize ATP, and endogenous ATPases destroy the remaining ATP; thus, ATP levels drop precipitously.

Cells were seeded at a density of 3000-5000 cells/well (depending on cell lines) in 90 µl of residual medium on MTP (Corning; #3603, black plate, clear flat bottom). For each cell line tested, cells were seeded in a separate plate for fluorescence determination at t = 0 h and t = 72 h (time points). After overnight incubation at 37°C, chemiluminescence values for samples at t = 0 were determined after adding 10 µl medium and 100 µl CTG solution according to the manufacturer's protocol. Plates for the time points of t = 72 were treated with compounds diluted in the rest of the medium to ten final concentrations added in 10 µl to the cell culture plate. The cells were then incubated for 72 h at 37° C. Chemiluminescence values were determined for the samples at t = 72 h. For data analysis, in brief, 24-hour plate data were used to reflect 100% residual inhibition ("Ci") and a DMSO control was used for non-inhibited growth ("CO"), all analyzed using the MTS software package to determine IC 50 and Hill's coefficient. The experiments were controlled with the help of a reference compound (standard).

Preferred compounds of the present invention in this assay show cell growth inhibition of cell lines such as the KPL-4 breast tumor line and the MCF-7 breast tumor line (PIK3CA<E542K>E545K, hormone-dependent) and the LNCaP prostate tumor line with a median IC 50 of <10 pM, preferably a median IC 50 <1 pM.

The following Table shows selected data for selected Examples of this invention.

Example 5.0 - Caco2 permeability test

Caco-2 cells (obtained from DSMZ Braunschweig, Germany) were seeded at a density of 4.5 x 10<4> cells per well on 24-well insert plates (pore size 0.4 pm) and cultured for 15 days in DMEM medium supplemented with 10% fetal bovine serum, 1% GlutaMAX (100x, GIBCO), 100 U/ml penicillin, 100 pg/ml streptomycin (GIBCO) and 1% non-essential amino acids (100x). Cells were maintained at 37°C in a humidified atmosphere with 5% CO2. The medium was changed every 2-3 days. Before performing the permeation assay, the culture medium was replaced with FCS-free Hepes-carbonate transport buffer (pH 7.2). To evaluate the integrity of the monolayer, the transepithelial electrical resistance (TEER) was measured. Tested compounds were previously dissolved in DMSO and added to the apical or basolateral compartment with a final concentration of 2 pM. Samples were taken from both compartments before and after 2 h of incubation at 37°C. The analysis of the compound content was carried out after precipitation with methanol with the help of LC/MS/MS analysis. Permeability (Papp) was calculated in the apical-basolateral (A-+B) and basolateral-apical (B->A) direction. Apparent permeability was calculated using the following equation:

Papp = (Vr/P0)(1/S)(P2/t)

where Vr is the volume of the medium in the receiving chamber, P0 is the measured area of the spike of the tested drug in the donor chamber at t=0, S is the area of the monolayer, P2 is the measured area of the spike of the tested drug in the acceptor chamber after 2 h of incubation, and t is the incubation time. The ratio of basolateral (B) leakage to apical (A) leakage was calculated by dividing Papp B-A by Papp A-B. In addition, compound recovery was calculated. As a control, reference compounds were also analyzed in parallel.

Example 6.0 - in vivo pharmacokinetics in rats

For the purposes of in vivo pharmacokinetic experiments, the tested compounds were administered intravenously to male VVistar rats in doses of 0.5 to 1 mg/kg, and intragastrically in doses of 1 to 10 mg/kg, whereby the doses were formulated as solutions using a solubilizer such as PEG400 in well-tolerated amounts.

For pharmacokinetics after intravenous administration, the tested compounds were administered as i.v. bolus, and blood samples were taken at 2 min, 8 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after dosing. Depending on the expected half-life, additional samples were taken later (eg, 48 h, 72 h). For pharmacokinetics after intragastric administration, test compounds were administered intragastrically to fasted rats, and blood samples were taken at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after dosing. Depending on the expected half-life, additional samples were taken later (eg, 48 h, 72 h). Blood was collected in lithium-heparin tubes (Monovetten<®>, Sarstedt) and centrifuged for 15 min at 3000 rpm. An aliquot of 100 pl was taken from the supernatant (plasma) and was precipitated by adding 400 pl of cold acetonitrile and frozen at -20°C overnight. The samples were subsequently thawed and centrifuged at 3000 rpm at 4°C for 20 min. Aliquots of the supernatant were dissolved for analytical testing using an Agilent 1200 HPLC system with LCMS/MS detection. PK parameters were calculated with the help of non-compartmental analysis using PK calculation program.

PK parameters were derived from the concentration-time profile after i.v.: CLpIasm: Complete disappearance of the tested compound from plasma (in L/kg/h); CLblood: Complete disappearance of the tested compound from the blood: CLplasma<*>Cp/Cb (in L/kg/h) in relation to Cp/Cb is the ratio of concentrations in plasma and in blood. PK parameters calculated from the concentration-time profile after i.g.: Cmax: Maximum plasma concentration (in mg/L); Cmaxnorm: Cmax divided by the administered dose (in kg/L); Tmax: Time point at which Cmax was observed (in h). Parameters calculated from both concentration-time profiles, i.v. and i.g.: AUCnorm: Area under the concentration-time curve at t=0 h towards infinity (extrapolated) divided by the administered dose (in kg<*>h/L); AUC(0-tlast)norm: Area under the concentration-time curve at t=0 h until the last time point at which plasma concentrations can be measured divided by the administered dose (in kg<*>h/L); t1/2: terminal half-life (in h); F: oral bioavailability: AUCnorm after intragastric administration divided by AUCnorm after intravenous administration (in %).

One of skill in the art is familiar with procedures by which the in vivo efficacy of a compound against cancer can be demonstrated. By way of illustration, the following example describes procedures for quantifying in vivo efficacy in a murine xenograft model. One skilled in the art can apply such principles with the goal of deriving models from alternative tumor material.

Example 7.0: Study of the mechanism of action in vivo xenotransplantation

In order to demonstrate that the mentioned compounds act in tumors through the predicted mode of action, the phosphorylation of AKT protein was investigated in KPL-4 breast tumors that were treated with 50 mg/kg of the compound. KPL-4 human mammary tumors were transplanted into thymus-deprived nude mice. KPL-4 tumor cells were cultured according to ATCC protocols in the intended medium containing 10% FCS and harvested for transplantation in a sub-confluent (70%) state. 3 x 106 tumor cells were suspended in 50% Matrigel and implanted subcutaneously in the inguinal region of female mice. Tumors were allowed to grow to the intended size of 60-80 mm<2>. When tumors reached approximate size, animals were randomly divided into treatment and control groups (group size: 9 animals), and treatment was initiated. Animals were treated once with 50 mg/kg of compound or vehicle by oral administration (p.o.) via gavage. The treatment of each animal is based on its individual body weight. At 2, 5 and 24 h post-treatment, 3 animals were sacrificed and KPL-4 tumors were removed. Tumor specimens approximately 5x5x5 mm in size were lysed on ice in MSD lysis buffer in the presence of protease and phosphatase inhibitors using a Tissue Analyzer (OJagen, Germany). p-AKT S473 levels in tumor tissue extracts were analyzed in an ELISA-based assay. This test is based on "Akt Duplex" from the MULTI-SPOT<®>Test System (Fa. Meso Scale Discoverv, Cat. #N41100B-1) according to the manufacturer's instructions. Each assay used 20 pg of protein extract, and total AKT and p-AKT content was measured in one well. All measurements were performed at least in duplicate and confirmed by independent repetition.

The values for P-AKT are expressed as a percentage of the P-AKT level in relation to the total AKT content of the extracts. Tumors treated with transporter alone were analyzed to determine the basal level of P-AKT in the aforementioned model and used as a normalized control to determine the percentage (%) of P-AKT relative to transporter levels.

Preferred compounds of the present invention shown in this assay: relative to P-AKT transporter levels <30% at 2 h post-treatment, better at 5 h post-treatment, and best at 24 h post-treatment.

Example 7.1: Efficacy study in vivo xenotransplantation

In order to determine the therapeutic efficacy and tolerability of the compound, the tumor growth of KPL-4 mammary tumors transplanted into nude mice can be observed. Mice were treated with vehicle or compounds. KPL-4 xenografts were established as previously described. Tumors were allowed to grow to the intended size of 25 - 35 mm<2>. When tumors reached approximate size, animals were randomly assigned to treatment and control groups (group size: 8 animals), and treatment was initiated. The treatment of each animal was based on individual body weight, and oral administration (p.o.) was carried out through a gastric tube. Volumes for oral administration of mice were 10 ml/kg. Mice were treated once daily with 50 mg/kg of the compound.

Tumor response was assessed by determining the tumor surface area (the product of the longest diameter and its vertical side) using a slide rule. Animal body weight was monitored as a measure of treatment-related toxicity. Measurements of tumor surfaces and body weights were carried out 2-3 times a week. Statistical analysis was carried out with the help of the SigmaStat program. A one-way analysis of variance was performed, and differences compared to the control were analyzed using the pair-wise comparison procedure (Dunn's procedure). T/K ratios (Treatment/Control) were calculated using the final tumor weights at the end of the study.

Claims (14)

1. Compound of formula (I) indicated by the fact that R 1 is hydrogen, hydroxy, NR 5 R 6 , halogen, cyano, CO(NR 8 R 9 ), C(O)OR<B>. C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(0)NHR11. -S(0)n-1-6C-alkyl, -S(0)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -0-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl, wherein said group is optionally substituted, one or more times, the same or differently, with a substituent selected from the group containing: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl. 1-6C-Alkoxy, -NR8R9, Cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11. -NHC(0)NHR11. -NHS(0)2R11, 3-7C-cycloalkyl, 3-7C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHC(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-6C-alkyl, -S(0)2NR5R6 or a group selected from the group consisting of 1-6C-alkyl, 1-6C-Alkoxy, 3-7C-Cycloalkyl, Aryl, Heteroaryl. -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -0-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl, wherein said group is optionally substituted, one or more times, the same or differently, with a substituent selected from the group consisting of: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-7C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl). NHS(O)2R11, NHC(0)NHR11, -S(0)"-1-6C-alkyl. -S(0)2NR5R6 or a group selected from the group consisting of 1-6C-alkyl, 1-6C- alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -0-(3-7C-cycloalkyl), -O-aryl, -0-(3-7C-heterocyclyl), -O-heteroaryl, -O-(1-6C-alkyl)-heteroaryl, -0-(1-6C-alkyl)-(3-7C-heterocyclyl), -0-(1-6C-alkyl)-aryl, NHC(0)(1-6C-alkyl), 2-6C-alkenyl. 2-6C-alkynyl, wherein said group is optional substituted, once or more, identically or differently, with a substituent selected from the group consisting of: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, - C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, -NHS(0)2R11, 3-7C-heterocyclyl, aryl, R 4 is phenyl optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, 1-6C-alkyl, R6 is hydrogen, 1-6C-alkyl, R8 is hydrogen, 1-6C-alkyl optionally substituted with hydroxy, R9 is hydrogen, 1-6C-alkyl, R 10 is hydrogen, 1-6C-alkyl, Rll is hydrogen, 1-6C-alkyl, X,Y is CH2; her 0, 1, 2; or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 2. The compound according to claim 1 indicated by the fact that R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHC(0)(1-6C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)„-1-3C-alkyl. -S(0)2NR5R6 or a group selected from the group consisting of 1-3C-alkyl, 1-3C-Alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -0-(3-6C-cycloalkyl), -O-aryl, -0-(3-6C-heterocyclyl), -O-heteroaryl, -0-(1-3C-alkyl)-heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), -O-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl, wherein said group is optionally substituted, one or more times, the same or differently, with a substituent selected from the group consisting of: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, -C(0)NR8R9, -C(O)OR10, -NHC(0)R11, -NHC(0)NHR11, - NHS(0)2R11, 3-6C-cycloalkyl, 3-6C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(O)(1-3C-alkyl). NHC(O)(1-3C-alkyl), NHS(O)2R11, NHC(O)NHR11. -S(0)„-1-3C-alkyl. -S(0)2NR5R6 or a group selected from the group consisting of 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl. -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -0-(3-6C-cycloalkyl), -O-aryl, -O-(3-6C-heterocyclyl), -O-heteroaryl, -O-(1-3C-alkyl)-heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), -O-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl. wherein said group is optionally substituted, one or more times, the same or differently, with a substituent selected from the group containing: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl. 1- 3C-Alkoxy, -NR8R9, Cyano, -C(O)NR8R9, -C(O)OR10, -NHC(O)R11. -NHC(0)NHR11, - NHS(0)2R11, 3-6C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(0)OR8, C(0)(1-3C-alkyl), NHS(0)2R11, NHC(0)NHR11, -S(0)n-1-3C-alkyl, -S(0)2NR5R6 or a group selected from the group consisting of 1-3C-Alkyl, 1-3C-Alkoxy, 3-6C-Cycloalkyl, Aryl, Heteroaryl, -(1-3C-Alkyl)-Aryl, -(1-3C-Alkyl)-Heteroaryl, -O-(3-6C-Cycloalkyl), -O-Aryl, -O-(3-6C-Heterocyclyl), -O-Heteroaryl, -O-(1-3C-Alkyl)-Heteroaryl, -0-(1-3C-alkyl)-(3-6C-heterocyclyl), -0-(1-3C-alkyl)-aryl, NHC(0)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group is optionally substituted, one or more times, the same or differently, with a substituent selected from the group consisting of: hydroxy, halogen, 1-3C-alkyl, 1-3C-Haloalkyl, 1-3C-Alkoxy, -NR8R9, cyan. -C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NIIC(0)NHR11, -NHS(O)2R11, 3-6C-heterocyclyl. aryl, R 4 is phenyl optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, 1-3C-alkyl, R6 is hydrogen, 1-3C-alkyl, R8 is hydrogen, 1-3C-alkyl optionally substituted with hydroxy, R9 is hydrogen, 1-3C-alkyl, R10 is hydrogen, 1-3C-alkyl, R11 is hydrogen, 1-3C-alkyl, X, Y is CH2; her 0, 1,2; or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 3. A compound according to claim 1 indicated by the fact that R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(0)OR8, NHC(0)(1-6C-alkyl), or a group selected from the group consisting of 1-6C-alkyl, 3-7C-cycloalkyl, aryl, heteroaryl, 1-4C-alkoxy, wherein said group is optionally substituted, one or more times, the same or differently, with a substituent selected from the group consisting of: halogen, 1-6C-alkyl, 1-6C-Alkoxy, - C(O)OR10, 3-7-cycloalkyl, aryl, R2 is hydrogen, 1-6C-alkyl, R3 is hydrogen, hydroxy, NR5R6, halogen, CO(NR8R9), C(0)OR8, C(0)(1-6C-alkyl), NHS(0)2R11, S(0)n-1-6C-alkyl, or a group selected from the group consisting of 1-6C-alkyl, 1-6C-Alkoxy aryl, NHC(0)(1-6C-alkyl), 2-6C-alkenyl, wherein said group is optionally substituted, one or more times, the same or differently, with a substituent selected from: halogen, -C(O)OR10, R4 is phenyl, R5 is hydrogen, R6 is hydrogen, R8 is hydrogen, 1-4C-alkyl, which is optionally substituted with hydroxy, R9 is hydrogen, 1-4C-alkyl, R10 is, 1-4C-alkyl, R11 is 1-4C-alkyl, X, Y is CH2 her 0, 1,2; or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 4. A compound according to claim 1 indicated by the fact that R1 is hydrogen, hydroxyl, amino, methoxy, ethoxy, butoxy, pyridin-3-yl, pyridin-4-yl, pyrazol-3-yl, l-methyl-pyrazol-3-yl, imidazol-2-yl, methyl, propyl, -0-(CH2)-0-CH3, -0-CH2-phenyl, -0-CH2-cyclopropyl, -C(0)OHCH3, -C(0)-NHCH3. -C(0)-NH2, 4-fluoro-phenyl, -(CH2)2-C(0)OCH3, cyclopropyl, -NH-C(0)CH3, R2 is hydrogen, methyl, R3 is hydrogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, -0-CH2-C(0)OCH3, -S-CH3, -SO2-CH3, bromine, chlorine, trifluoromethyl, C(0)NH2, COOH,C(0)OCH3, C(0)OCH2CH3, C(0)NH2, C(0)NHCH3, C(0)N(CH3)2, C(0)NH(CH2)2-OH, -CH=CH2, 4-fluoro-phenyl, NHC(0)CH3, NHC(0)CF3, NH-S02-CH3, C(0)CH3 R 4 is phenyl X, Y is CH2 or an N-oxide, salt, tautomer or stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 5. A compound according to claim 1, characterized in that it is selected from the group consisting of 6. The compound according to claim 5, characterized in that it is selected from the group consisting of 7. A compound according to claim 5, characterized in that it is selected from the group consisting of 8. Process for the production of compounds of the general formula (I) according to claim 1 by reaction compounds of general formula (II) indicated by the fact that R1-R4 have the meaning as set forth in claim 1 and Rx, Ry are R6, or a protecting group, wherein the transformation to the compound of general formula (I) is achieved using a suitable deprotection reaction. 9. A compound according to claim 1 for use in the treatment of a disease. 10. The compound for use according to claim 9, characterized in that the disease is benign neoplasia or malignant neoplasia. 11. The compound according to claim 1-7 for use in the treatment of breast cancer. 12. Pharmaceutical composition characterized by comprising at least one compound with the general formula (I) according to any one of claims 1 to 7, together with at least one pharmaceutically acceptable excipient. 13. Pharmaceutical composition characterized by including the first active substance. which is at least one compound with the general formula (I) according to any one of claims 1 to 7, and another active substance, which is at least one additional anticancer agent. 14. The composition according to claim 12 or 13, characterized in that it is for use in the treatment of breast cancer.